ES2954361T3 - Methods of using dipivefrin - Google Patents

Abstract

The disclosure provides a method for systemic administration of a therapeutically effective amount of epinephrine to a subject comprising orally administering dipivephrine or a salt of dipivephrine to the subject. The disclosure also includes a method of treating a disease amenable to treatment by in vivo administration of systemic epinephrine comprising administering dipivephrine or a salt of dipivephrine to a subject requiring in vivo administration of systemic epinephrine. The disease may be a respiratory disorder, anaphylaxis, cancer, or a microbial infection. The disclosure also includes orally dissolving dipivefrin or dipivefrin HCl tablets. (Automatic translation with Google Translate, without legal value)

Description

DESCRIPTION

Methods of using dipivefrin

Background

This description relates to dipivephrine, a prodrug of epinephrine, for safely and rapidly administering systemic epinephrine.

Epinephrine, also known as adrenaline, is a hormone and neurotransmitter produced naturally by both the adrenal glands and certain neurons. It is widely used, in injectable form, to treat anaphylaxis, a severe allergic reaction, asthma attacks, and to restore normal heart rhythm during cardiac arrest. For example, EP 2 085 071 describes liquid oral compositions of epinephrine for use in the treatment of anaphylaxis; US 2007/202163 describes buccal and sublingual epinephrine tablets for use in the treatment of anaphylaxis; and WO 2007/143676 describes buccal and injectable epinephrine compositions for use in the treatment of anaphylaxis.

Additionally, injectable epinephrine has been shown to be effective in preventing and treating cancer. United States Patent No. 5,925,682 describes that injection into a mammal of an effective amount of epinephrine results in a significant reduction in tumor growth.

Regular exercise has also been shown to reduce the risk of a wide spectrum of cancers and cancer recurrence, including breast cancer, colon and rectal cancer, pancreatic cancer, prostate cancer, endometrial cancer , ovarian cancer and lung cancer. One mechanism behind this protection may be due to the fact that exercise stimulates the secretion of epinephrine. Pedersen et al (Cell Metabolism, 23, 1-9, March 8, 2016) found that exercise reduces tumor incidence and growth by more than 60% in several mouse tumor models through direct regulation of mobilization and trafficking of NK cells in an epinephrine- and IL-6-dependent manner.

The biological and pharmacological effects of epinephrine occur through its binding to alpha and beta adrenergic receptors. The distribution of adrenergic receptors in different cells explains the multitude of effects of epinephrine. The binding of epinephrine to alpha receptors results in dilation of blood vessels in skeletal muscles and the liver.

Epinephrine can cause increases in heart rate and blood pressure. These effects are dangerous and therefore limit the available use of epinephrine treatments.

The clinical dose of epinephrine administered intravenously is usually much lower than that administered by intramuscular or subcutaneous injection. Additionally, the effects of epinephrine injected intravenously differ from the effects of subcutaneous injection or slow intravenous infusion of the compound. This is believed to be due to slow absorption of epinephrine injected subcutaneously due to the local vasoconstrictive action of the drug. In fact, the effects of subcutaneously injected doses of up to 0.5 to 1.5 mg of epinephrine can be doubled by an intravenous infusion of as little as 10-30 pg/min. Additionally, epinephrine cannot be administered orally.

Oral epinephrine is not well absorbed. All drugs taken orally enter the liver through the hepatic portal circulation before entering the systemic circulation. The hepatic portal circulatory system is the venous drainage of the upper GI tract, transporting molecules absorbed by the intestine to the veins leading to the liver. Epinephrine is a catecholamine, a class of monoamine compounds that has a catechol and an amine side chain. Epinephrine is known to be inactivated by two enzymes: monoamine oxidase (MAO) and catechol-O-methyltransferase (COMT). MAO oxidizes the side chain amine and COMT acts on the catechol part of epinephrine. MAO and COMT are present in the liver and intestinal wall. Both enzymes are highly active and rapidly destroy orally administered epinephrine before it reaches the systemic circulation.

Various needle-free approaches have been attempted to deliver epinephrine systemically for anaphylaxis, for example, inhalation, sublingual, and intranasal routes. Inhaled epinephrine has been shown to be ineffective when used in children because the number of epinephrine inhalations required and the poor taste of inhaled epinephrine mean that most children cannot inhale enough epinephrine to reach the therapeutic concentration safely. fast and significant. A study in rabbits showed that epinephrine administered sublingually can be absorbed systemically in an amount equivalent to IM epinephrine. However, the equivalent sublingual dose (40 mg) was about 100 times higher than the usual IM dose (0.3 mg). The large dose required for the sublingual route is likely due to its enzymatic mucosal degradation by COMT, as well as poor intrinsic mucosal transport due to the strong vasoconstriction caused by epinephrine itself.

Intranasal administration of epinephrine for anaphylaxis has been described in United States patent application US 2015/0005356 A1 and the references cited therein. But to overcome the mucosal enzymatic degradation by COMT, as well as the poor intrinsic mucosal transport due to the strong vasoconstriction caused by epinephrine itself, a reversible catechol-O-methyl transferase (COMT) inhibitor and a vasodilator are required, which can cause serious side effects. A nasal spray with a high loading dose of epinephrine (5 mg) dissolved in normal saline without a reversible catechol-O-methyl transferase (COMT) inhibitor and a vasodilator was administered to normal human subjects and compared with epinephrine. intramuscular in a recent study by Srisawat C. and others Asian Pac. J. Allergy Immunol. (2016) 34:38-43. The study revealed a maximum plasma concentration (Tmax) achieved in 70 ± 17 minutes. A Tmax of 70 ± 17 minutes, even with the highest loading dose of epinephrine, is insufficient to be of any use in anaphylactic shock. Paradoxically, the PK data from 1 M epinephrine injection with a Tmax of 67 ± 43 minutes are also unacceptable.

There remains a need in the art for methods of systemic administration of epinephrine that are safer and more convenient than current injectable formulations of epinephrine for the treatment of various diseases such as anaphylaxis. There is also a need for a method of administering epinephrine that provides low systemic absorption, to reduce the occurrence of side effects.

Summary of the invention

Dipivephrine is a dipivaloyl ester prodrug of epinephrine. Dipivefrin hydrochloride has been approved for ocular use as a 0.1% ophthalmic solution indicated as initial therapy for the control of intraocular pressure in chronic open-angle glaucoma. Dipivephrine is biotransformed to epinephrine at the site of administration (the eye) by enzymatic hydrolysis with low systemic absorption of epinephrine.

The inventor has surprisingly discovered that dipivephrine can safely and effectively deliver epinephrine to the systemic circulation when taken orally.

In a first aspect of the invention, dipivephrine or a pharmaceutically acceptable salt thereof is provided for use in a method of systemic delivery of a therapeutically effective amount of epinephrine to a subject, where in said method said dipivephrine or a salt thereof or a pharmaceutically acceptable salt thereof is administered orally.

In some embodiments, the subject has anaphylaxis; shortness of breath associated with asthma, bronchitis, emphysema, diphtheria, or respiratory infection; cancer; or a microbial infection, such as a bacterial, viral, fungal or parasitic infection.

In some embodiments, the subject has anaphylaxis and the therapeutically effective amount of epinephrine is: (i) an amount sufficient to relieve at least one symptom of anaphylaxis in the subject; or (ii) an amount sufficient to reduce the severity of anaphylaxis or inhibit the occurrence of anaphylaxis in the subject upon exposure of the subject to an allergen.

In some embodiments, the subject has cancer. In some such embodiments, the cancer is skin cancer, brain cancer, a glioma, a sarcoma, breast cancer, lung cancer, non-small cell lung cancer, mesothelioma, appendiceal cancer, a genitourinary cancer, a cell carcinoma. kidney, prostate cancer, bladder cancer, testicular cancer, penile cancer, cervical cancer, ovarian cancer, von Hippel Lindau disease, head and neck cancer, gastrointestinal cancer, hepatocellular carcinoma, liver cancer gallbladder, esophageal cancer, gastric cancer, colorectal cancer, pancreatic cancer, a neuroendocrine tumor, a thyroid tumor, a pituitary tumor, an adrenal tumor, a hematological malignancy, a lymphoma, a leukemia, or a combination of these.

In some embodiments, dipivefrin or its pharmaceutically acceptable salt is an adjuvant antineoplastic treatment and the method comprises administering at least one additional antineoplastic treatment to the subject.

In some embodiments, the subject has a microbial infection. In some such embodiments, the infection is a flu infection or a methicillin-resistant Staphylococcus aureus (MRSA) infection. In some such embodiments, dipivephrine or its pharmaceutically acceptable salt is an adjuvant antimicrobial agent and the method further comprises the use of at least one additional antimicrobial agent, such as an antibiotic or an antiviral agent, to treat the infection in the subject.

In some embodiments, dipivefrin in L-dipivefrin hydrochloride.

In some embodiments, dipivefrin or a salt thereof is administered as an oral dosage form, wherein dipivefrin is in the form of an oral solution, a tablet or a capsule. In some such embodiments, the dipivefrin or a salt thereof is in the form of an orally dissolving tablet or an orally disintegrating tablet. In some such embodiments, dipivefrin is in the form of a dissolving tablet. oral comprising dipivephrine or one of its salts in a matrix that can dissolve in the oral cavity in 2 minutes or less. In some such embodiments, the tablet additionally comprises a water-soluble polymer, such as gelatin, HPMC or a combination thereof, and a sweetener.

In some embodiments, dipivefrin or a salt thereof comprises a dosage form comprising 0.01 mg to 150 mg, 0.01 mg to 100 mg, 0.01 mg to 50 mg, 0.1 mg to 20 mg, 0.1 mg to 10 mg, 0.1 mg to 5 mg, 0.1 mg to 3 mg, 2.5 mg, 2 mg or 1.5 mg of dipivefrin.

In some embodiments, the subject is a human or a dog.

In some embodiments, the method provides a therapeutically effective amount of epinephrine within 30 minutes after administration, within 15 minutes after administration, within 10 minutes after administration, or within 5 minutes after administration. the administration.

The features described above and others are exemplified by the following figures and detailed description.

Brief description of the drawings

The following is a brief description of the drawings that are presented for the purpose of illustrating the illustrative embodiments described in the present description and not for the purpose of limiting them.

Figure 1 is a graph of the mean plasma concentration of epinephrine (epi) versus time in mice (N=3) after oral administration of 21.2 mg/kg dipivephrine hydrochloride (19.2 mg/kg free base; equivalent to 10 mg/kg racemic epinephrine).

Figure 2 is a graph of the mean plasma concentration of epinephrine versus time after an intraperitoneal (IP) administration of dipivephrine hydrochloride at 1.06 mg/kg (0.96 mg/kg free base, equivalent to 0 .5 mg/ml racemic epinephrine) in mice (N=3).

Figure 3A is a graph of mean plasma epinephrine concentration versus time in mice (N=3) after intramuscular (IM) injection with 0.636 mg dipivephrine hydrochloride (0.57 mg free base, equivalent to 0 .3 mg racemic epinephrine).

Figure 3B is a graph of mean plasma epinephrine concentration versus time in mice (N=3) after an IM injection of 0.546 mg epinephrine bitartrate (0.3 mg free base).

Figure 4 is a graph of the mean body weight of mice from all treatment groups as a function of study day.

Figure 5 is a bar graph showing the mean B16F10 tumor volume, 5 days after inoculation of tumor cells into mice.

Figure 6 is a bar graph showing the median B16F10 tumor volume, 14 days after inoculation of tumor cells into mice.

Figure 7 is a bar graph showing the mean B16F10 tumor volume for treatment with dipivefrin versus vehicle after the tumor was established.

Figure 8 is a graph showing the percentage of survival as a function of study time (Kaplan-Meier curves) for groups 1a, 1b and 2.

Figure 9 is a graph showing bacteria levels in the blood 4 hours after MRSA infection.

Figure 10 Effect of a single oral dose of dipivefrin HCl on the body weight of mice during influenza A/California/04/2009 H1N1pdm virus infection in C57BL/6J mice. A dose of dipivefrin HCl was administered p.o. 24 hours after exposure to the virus at 8.48 mg/kg. Graph represents mean weight per percentage of initial body weight (day 0) ± SEM. * p < 0.05.

Figure 11 Effect of a single oral dose of dipivefrin HCl on lung viral titers during influenza A/California/04/2009 H1N1pdm virus infection in C57BL/6J mice. A single dose (8.48 mg/kg) of dipivefrin HCl was administered p.o. 24 hours after exposure to the virus. Lung tissue was removed from 3 mice in each treatment group on day 3 and day 6 after inoculation, and influenza virus titers were determined by endpoint titration.

Figure 12 Mean plasma epinephrine concentration versus time profiles after a single oral dose of dipivefrin HCl oral solution 63.6 mg and dipivefrin HCl oral solution 6.36 mg in rabbits.

Figure 13 Profiles of mean plasma epinephrine concentration versus time after a single oral dose of dipivefrin HCl orally dissolving tablet form 63.5 mg and dipivefrin HCl oral solution form 63.6 mg in rabbits.

Figure 14 Mean plasma epinephrine concentration versus time profiles after a single oral dose of dipivefrin HCl as an orally dissolving tablet 63.5 mg and IM injectable epinephrine 0.3 mg in rabbits.

Figure 15 Mean plasma epinephrine concentration versus time profiles after a single oral dose of dipivefrin HCl as an orally dissolving tablet 5 mg and epinephrine as a single standard IM injection 0.3 mg in beagle dogs (crossover design, N = 3).

Figure 16. Mean plasma epinephrine concentration versus time profiles after a single oral dose of dipivephrine HCl as orally dissolving tablets 5 mg and 63.5 mg in beagle dogs (crossover design, N = 3).

Detailed description

Administration of dipivephrine has been found to be effective for the safe and rapid systemic administration of epinephrine to a subject. Administration of dipivefrin may be by any appropriate route, for example, oral administration or injection. Several diseases are amenable to treatment with systemic epinephrine, such as anaphylaxis, cancer, and microbial infections, however, safe and convenient means of administering epinephrine to individuals have been problematic. In particular, epinephrine has been limited to administration by injection due to lack of oral absorption, a route that is less convenient than oral dosing.

The inventor has surprisingly discovered that dipivephrine can safely and effectively deliver epinephrine to the systemic circulation when taken orally. This result was not expected because, first, although unlike epinephrine, dipivephrine does not possess a free catechol group, making it an unlikely substrate of catechol-O-methyltransferase (COMT), it was still expected. conversion to epinephrine via hydrolysis of the ester during transition through the GI tract and subsequent degradation of the resulting epinephrine by COMT. Second, dipivephrine has the same side-chain amine functional group as epinephrine, which could be inactivated by the same monoamine oxidase (MAO) present in both the gastrointestinal tract and liver that is responsible for the inactivation of epinephrine. orally. Third, even if dipivephrine reaches the systemic circulation after oral administration, there is no guarantee that it will be biotransformed to epinephrine in a sufficiently timely and efficient manner to be effective as a therapeutic agent. Biotransformation of prodrugs in vivo requires the presence of appropriate enzymes that are often species-specific and tissue-specific. Therefore, the inventor was surprised to discover that dipivephrine can safely and effectively deliver epinephrine to the systemic circulation when administered orally.

Surprisingly, administration of dipivephrine, including oral administration, is shown to be effective for the safe and rapid systemic delivery of epinephrine to a subject and for the treatment of anaphylaxis, cancer and microbial infection.

The present disclosure provides compositions for use in a method of systemic delivery of epinephrine to a subject as a result of oral administration of dipivephrine or a pharmaceutically acceptable salt thereof. In some embodiments, the subject has anaphylaxis, a difficulty breathing associated with asthma, bronchitis, emphysema, diphtheria, or respiratory infection; cancer or a microbial infection. In some embodiments, the subject is a human subject in need of such treatment. Furthermore, the present disclosure provides novel therapeutic approaches to treat anaphylaxis, cancer or a microbial infection based on therapeutic regimens using dipivephrine administered orally alone, as monotherapy or in combination with at least one additional therapeutic agent, such as an antineoplastic agent or an antimicrobial agent.

In some embodiments, the dipivefrin composition comprises dipivefrin free base or dipivefrin hydrochloride.

Terminology

As used herein, the term "dipivefrin composition" refers to a composition comprising dipivefrin (free base), or may encompass salts, solvates, clathrates, polymorphs, analogues or pharmaceutically acceptable derivatives of dipivefrin, as described below. A preferred dipivefrin composition comprises dipivefrin or dipivefrin hydrochloride.

The structure of dipivephrine is shown in Formula (I).

The IUPAC name of dipivephrine is 4-(1-hydroxy-2-(methylamino)ethyl)-1,2-phenylene bis(2,2-dimethylpropanoate). Synonyms of dipivephrine are [±] -3,4-dihydroxy-a-[(methylamino)methyl]benzyl alcohol 3,4-dipivalate, 1-(3',4'-dipivaloyloxyphenyl)-2-methylamino-1-ethanol , 4-[1-hydroxy-2-(methylamino)ethyl]-O-phenylene divavalate, dipivalyl epinephrine and

[2-(2,2-dimethylpropanoyloxy)-4-[1-hydroxy-2-(methylamino)ethyl]phenyl] 2,2-dimethylpropanoate. Dipivefrine has the no. reg. CAS 52365-63-6. Dipivefrin hydrochloride has no. reg. CAS 64019-93-8.

Dipivephrine and its pharmaceutically acceptable salts can be prepared, for example, according to the methods described in United States Patent No. 3809714.

As used herein, the term "pharmaceutically acceptable salt" is a salt formed, for example, from an acid and a basic group of a dipivephrine composition. Illustrative salts include, but are not limited to, salts of sulfate, citrate, acetate, oxalate, chloride, acid chloride, bromide, iodide, nitrate, phosphate, acid phosphate, isonicotinate, lactate, salicylate, acid citrate, tartrate, oleate, tannate, pantothenate, bitartrate, ascorbate, succinate, maleate, besylate, gentisinant, fumarate, gluconate, glucaronate, saccharate, formate, benzoate, glutamate, methanesulfonate, ethanesulfonate, benzenesulfonate, p-toluenesulfonate and pamoate (e.g., 1,1'- methylene-bis-(2-hydroxy-3-naphthoate)). In one embodiment, the dipivefrin salt is a hydrochloride salt. Unless clearly contraindicated by the context, "dipivefrin" includes the pharmaceutically acceptable salts of dipivefrin.

The term "pharmaceutically acceptable salt" further refers to a salt prepared from a composition having an acidic functional group, such as a carboxylic acid functional group, and a pharmaceutically acceptable inorganic or organic base.

The term "pharmaceutically acceptable salt" further refers to a salt prepared from a composition having a basic functional group, such as an amino functional group, and a pharmaceutically acceptable inorganic or organic acid.

An "active agent" means a compound (including, for example, dipivephrine), element or mixture that, when administered to a subject, alone or in combination with another compound, element or mixture, confers, directly or indirectly, an effect physiological on the subject. The indirect physiological effect may occur through a metabolite or another indirect mechanism.

The terms "administer", "administer", "administered" or "administration" refer to any way of providing an active agent (such as dipivefrin or a pharmaceutically acceptable salt thereof) to a subject or patient. Routes of administration can be achieved through any means known to those skilled in the art. Such means include oral, buccal, intravenous, subcutaneous, intramuscular, transdermal and inhalation, sublingual, intranasal. Oral administration is a preferred route of administration for dipivefrin.

The terms "taken orally" and "oral administration" refer to a way of providing an active agent to a subject or patient by mouth through the gastrointestinal tract (digestive system, digestive tract, GI tract, GIT, intestine or alimentary canal) and are used interchangeably. The gastrointestinal tract is an organ system within humans and other animals that ingests food, digests it to extract and absorb energy and nutrients, and expels the remaining waste as feces. The mouth, esophagus, stomach, and intestines are part of the gastrointestinal tract.

A "dosage form" means a unit of administration of an active agent. Examples of dosage forms include tablets, capsules, oral thin films, orally dissolving (or disintegrating) dosage forms, sprays, injections, suspensions, liquids, emulsions, creams, ointments, suppositories, inhalable forms, transdermal forms , intranasal spray and the like.

An “orally dissolving (or disintegrating) dosage form” is a solid dosage form that disintegrates or dissolves quickly, usually within seconds, when placed in the mouth. Orally dissolving dosage forms are designed to disintegrate or dissolve rapidly upon contact with saliva, eliminating the need to chew, swallow, or take the solid dosage with water. An oral dissolution dosage may promote pregastric absorption of active ingredients across the buccal, sublingual, oropharyngeal, and esophageal membranes. As a result, an oral dissolution dosage may provide a faster onset of action and greater bioavailability than a conventional solid dosage form.

"Pharmaceutical compositions" are compositions comprising at least one active agent, for example, dipivephrine, and at least one other substance, such as a carrier, excipient or diluent. The pharmaceutical compositions comply with the GMP (good manufacturing practices) standards of the United States FDA for drugs for human or non-human beings.

The term "carrier" as applied to the pharmaceutical compositions described herein refers to a diluent, excipient or vehicle with which an active compound is provided.

A "pharmaceutically acceptable excipient" refers to an excipient that is useful in the preparation of a pharmaceutical composition that is generally safe, non-toxic and that is not biologically or otherwise undesirable. mode, and includes an excipient that is acceptable for veterinary use as well as for human pharmaceutical use. A "pharmaceutically acceptable excipient" as used in the present application includes both one and more than one such excipient.

A "patient" is a human or non-human animal in need of medical treatment. Medical treatment may include treatment of an existing condition, such as a disease or disorder, prophylactic or preventive treatment, or diagnostic treatment. In some embodiments, the patient is a human patient. The patient may also be a livestock animal (eg, sheep, pig, horse, cow) or a companion animal (dog, cat).

The term "subject" includes a human being or any non-human animal. For example, the methods and compositions described herein can be used to administer systemic epinephrine to a subject in need thereof. In a particular embodiment, the subject is a human being. The subject may also be a livestock animal (e.g., sheep, pig, horse, cow) or a companion animal (dog, cat).

A "therapeutically effective amount" or "effective amount" is the amount of a pharmaceutical agent to achieve a pharmacological effect. The term "therapeutically effective amount" includes, for example, a prophylactically effective amount, that is, an amount effective to significantly reduce the probability of occurrence of a disorder in a patient at risk for the disorder. An "effective amount" of dipivefrin is an amount necessary to achieve a desired pharmacological effect or therapeutic improvement without undue adverse side effects. Those skilled in the art will select the effective amount of dipivefrin based on the particular patient and the type of conditions being treated. It is understood that "an effective amount" or "a therapeutically effective amount" may vary from patient to patient, due to variation in the general condition of the subject, the condition being treated, the severity of the condition being treated, and the judgment of the doctor in charge. When discussing a method of treating cancerous tissue, an effective amount includes an amount effective to have a statistically significant and favorable effect on the rate of proliferation of the patient's cancer over time or on the level of a biological marker for the cancer.

The terms "treat" and "treatment" mean the implementation of a therapy with the intention of reducing the severity or frequency of the symptoms, the elimination of the symptoms or the underlying cause, the prevention of the onset of the symptoms or their cause. underlying, or the improvement or repair of damage due to a disorder or disease. In certain embodiments, "treatment" includes prophylactic treatment, which consists of administering an amount of dipivephrine effective to significantly reduce the proliferation of cancerous tissue or reduce the possibility of infection by a microbial pathogen in a patient. In certain embodiments, the treatment includes inhibiting the onset of anaphylaxis or reducing the severity of allergy symptoms in a subject exposed to an allergen.

The terminology used in the present description is intended to describe particular embodiments only and is not intended to be limiting. As used herein, the singular forms "a", "an" and "the" include the plural forms, which include "at least one", unless the content clearly indicates otherwise. "Or" means "and/or." As used herein, the term "and/or" includes any and all combinations of one or more of the associated listed elements. It will further be understood that the terms "comprises" and/or "comprising" or "includes" and/or "which includes" when used in this description, specify the presence of characteristics, regions, integers, steps, operations, elements and/or established components, but do not exclude the presence or addition of one or more characteristics, regions, integers, stages, operations, elements, components and/or groups thereof.

Unless otherwise defined, all terms (including technical and scientific terms) used in the present description have the same meaning as commonly understood by one skilled in the art to which this description pertains. It will be further understood that terms, as defined in commonly used dictionaries, should be interpreted with a meaning that is consistent with their meaning in the context of the relevant art and the present description, and will not be interpreted in an idealized or overly idealized sense. formal unless expressly defined in this description.

Dipivephrine is a prodrug of epinephrine, a compound that has structure (II) below.

L-epinephrine has the no. reg. CAS 51-43-4.

The present invention describes dipivefrin or a pharmaceutically acceptable salt thereof for use in a method of systemic delivery of a therapeutically effective amount of epinephrine to a subject, wherein in said method said dipivephrine or a pharmaceutically acceptable salt thereof is administered orally.

The subject may have a disease amenable to treatment by in vivo administration of systemic epinephrine. Non-limiting examples of such diseases include allergic reaction, anaphylaxis, cancer and microbial infections. Dipivefrin can be administered as a pharmaceutical composition containing dipivefrin. Dipivephrine may be administered as an oral dosage form, such as an oral solution or suspension, a tablet (e.g., an orally dissolving/disintegrating tablet), a capsule, a spray, or a powder.

Anaphylaxis treatment

The subject may be experiencing anaphylaxis, and dipivephrine or a pharmaceutically acceptable salt thereof is administered orally, for example, in an oral tablet, capsule, solution, suspension or oral dissolving film. In one embodiment, the dipivefrin composition comprises dipivefrin free base or dipivefrin hydrochloride. The dipivephrine composition may be administered in an amount sufficient to provide a therapeutically effective plasma level of epinephrine in the subject. For example, an amount of dipivephrine sufficient to provide a plasma epinephrine level of 0.1 to 50 ng/ml. In some embodiments, a therapeutically effective amount of dipivephrine may be administered to a subject experiencing a less severe allergic reaction.

In one embodiment, the oral tablet is an orally dissolving tablet or an orally disintegrating tablet (ODT). An ODT is a solid dosage form containing medicinal substances that dissolve or disintegrate quickly, usually within seconds, when placed on the tongue. Characteristics exhibited by ODTs include low tablet weight, small tablet size, highly soluble components, and rapid dissolution or disintegration.

In one embodiment, the oral tablet is a fast-dissolving sublingual tablet. In certain embodiments, the oral tablet is not a sublingual tablet.

The therapeutically effective amount of a dipivefrin composition can be administered to a subject in less than 1 min, less than 2 min, less than 5 min, less than 10 min, less than 20 min or less than 30 min after the start of the anaphylaxis.

The therapeutically effective amount of a dipivefrin composition can be administered to the subject 6 hours before, 5 hours before, 4 hours before, 3 hours before, 2 hours before, 1 hour before, 30 min before, 10 min before or 5 min before a possible exposure to an anaphylaxis trigger for the subject.

An "anaphylaxis trigger" means a substance that causes an anaphylactic reaction in the subject. Examples of anaphylaxis triggers include foods, such as peanuts, tree nuts, fish, milk; certain medications, such as antibiotics (penicillins and cephalosporins) and pain relievers (aspirin, ibuprofen); venom from insects, including bees, yellowjackets, wasps, hornets, and fire ants; and natural rubber latex.

Cancer treatment

The subject in need may have cancer. The cancer may be, for example, a brain cancer, a glioma, a sarcoma, a skin cancer, a breast cancer, a lung cancer, a non-small cell lung cancer, a mesothelioma, an appendiceal cancer, a genitourinary, renal cell carcinoma, prostate cancer, bladder cancer, testicular cancer, penile cancer, cervical cancer, ovarian cancer, von Hippel Lindau disease, head cancer and neck, a gastrointestinal cancer, a hepatocellular carcinoma, a gallbladder cancer, an esophageal cancer, a gastric cancer, a colorectal cancer, a pancreatic cancer, a neuroendocrine tumor, a thyroid tumor, a pituitary tumor, a tumor adrenal gland, hematologic malignancy, lymphoma, leukemia, or a combination of these. Skin cancer can be melanoma, basal cell cancer, or squamous cell skin carcinoma.

In one embodiment, the cancer is a renal cell carcinoma.

In one embodiment, the cancer is breast cancer.

In one embodiment, the cancer is acute myeloid leukemia (AML) or acute lymphoblastic leukemia (ALL).

In one embodiment, the cancer is a B cell lymphoma.

In one embodiment, the cancer is a non-Hodgkins B cell lymphoma.

In one embodiment, the cancer is a glioma.

Dipivephrine or a salt of it may be used as part of combination therapy. As used herein, "combination therapy" includes the administration of a dipivefrin composition with at least one antineoplastic treatment in addition to dipivefrin, as part of a specific treatment regimen intended to provide a beneficial effect from the joint action of the composition of dipivefrin and additional antineoplastic treatment.

Therefore, dipivefrin can be administered with at least one additional antineoplastic treatment to a subject in need. Additional antineoplastic treatment may be surgery, chemotherapy, radiation, endocrine therapy, stem cell transplant, a molecularly targeted therapy, or a biological therapy. Examples of chemotherapeutics include anthracyclines such as doxorubicin and daunorribicin, taxanes such as paclitaxel and docetaxel, and platinum-based chemotherapies such as cisplatin and oxaliplatin. Examples of an endocrine therapy include tamoxifen, aromatase inhibitors, and androgen deprivation therapy for prostate cancer. Examples of a molecularly targeted therapy include hormonal therapies, signal transduction inhibitors, gene expression modulators, apoptosis inducers, angiogenesis inhibitors, immunotherapies, monoclonal antibodies that deliver toxic molecules, cancer vaccines, and gene therapy. . Examples of biological therapy include monoclonal antibodies or MAbs, cytokines, vaccines for cancer treatment, bacillus Calmette-Guerin (BCG) therapy, oncolytic virus therapy, gene therapy, and adoptive T cell transfer therapy.

In one embodiment, the at least one additional antineoplastic treatment may be an immunotherapy that uses certain parts of a person's immune system to combat diseases such as cancer. Examples of an immunotherapy include monoclonal antibodies, immune checkpoint inhibitors, cancer vaccines, cytokines and immunomodulatory drugs (or IMiDs), bacille Calmette-Guerin (BCG), imiquimod, and combinations of these. Examples of adoptive cell transfer therapy (ACT) include a cAr (chimeric antigen receptor) modified T cell therapy such as tisagenlecleucel and CAR modified NK cell therapy.

In one embodiment, the cancer vaccine is sipuleucel-T, approved for prostate cancer in the United States.

In one embodiment, at least one additional active agent may be administered to the subject. The at least one additional active agent may be a therapeutic agent or a non-therapeutic agent. The at least one additional active agent may be administered in a single dosage form with the dipivefrin composition, or in a dosage form separate from the dipivefrin composition. In one embodiment, the at least one additional active agent is selected from the group consisting of an alkylating agent, an intercalating agent, a tubulin binding agent, a corticosteroid and combinations thereof.

At least one additional active agent may be a therapeutic agent, for example, an antineoplastic agent or an anticancer chemotherapeutic agent, a non-therapeutic agent, or combinations thereof. With respect to therapeutic agents, the beneficial effect of the combination includes, but is not limited to, the joint pharmacokinetic or pharmacodynamic action resulting from the combination of therapeutically active compounds. With respect to non-therapeutic agents, the beneficial effect of the combination may relate to the mitigation of toxicity, a side effect, or an adverse event associated with a therapeutically active agent in the combination.

In one embodiment, the at least one additional active agent is a therapeutic agent. In one embodiment, the therapeutic agent is an antineoplastic agent. In one embodiment, the antineoplastic agent is a Bruton's tyrosine kinase (BTK) inhibitor such as ibrutinib. In one embodiment, a dipivefrin composition is administered together with ibrutinib in a single dosage form or in separate dosage forms. In one embodiment, the dosage form is an oral dosage form. In another embodiment, the dosage form is suitable for intravenous administration.

In one embodiment, the antineoplastic agent is a drug that is approved for use in the treatment of lymphoma. Non-limiting examples of such medications include abitrexate (methotrexate), adcetris (brentuximab vedotin), ambochlorin (chlorambucil), ambochlorin (chloramucil), arranon (nelarabine), becenum (carmustine), beleodaq (belinostat), belinostat, bendamustine hydrochloride, bexxar (tositumomab and iodine I 131 tositumomab), BiCNU (carmustine), blenoxane (bleomycin), bleomycin, brtezomib, brentuximab vedotin, carmubris (carmustine). Carmustine, chlorambucil, clafen (cyclophosphamide), cyclophosphamide, cytoxan (cyclophosphamide), denileukin diftitox, DepoCyt (liposomal cytarabine), doxorubicin hydrochloride, folex (methotrexate), folotyn (pralatrexate), ibritumomab tiuxetan, ibrutinib, idelalisib, imbruvica (ibtrutinib) , intron A (recombinant interferon alfa-2b), istodax (romidepsin), lenalidomide, leukeran (chlorambucil), lympholizine (chlorambucil), liposomal cytarabine, mechlorethamine hydrochloride, methotrexate, methotrexate LPF (methotrexate), mexate (methotrexate), mexate - AQ (methotrexate) mozobil (perixafor), mustargen (mechlorethamine hydrochloride), nelarabine, neosar (cyclophosphamide), ontak (denifleukin diftitox), perixafor, pralatrexate, prednisone, recombinant interferon alfa-2b, revlimid (lenalidomide), rituxan (rituximab) , rituximab, romidepsin, tositumomab and iodine I 131 tositumomab, treanda (bendamustine hydrochloride), velban (vinblastine sulfate), velcade (bortezomib), velsar (vinblasinte sulfate), vinblastine sulfate, vincasar PFS (vincristine sulfate), vincristine sulfate , vorinostat, zevalin (ibritumomab triuxetan), zolinza (vorinostat), and zydelig (idelalisib). In one embodiment, the antineoplastic agent is selected from an EZH2 inhibitor, for example, EPZ-6438. In one embodiment, the antineoplastic agent is selected from taxol, vincristine, doxorubicin, temsirolimus, carboplatin, ofatumumab, rituximab and combinations thereof.

In one embodiment, the at least one additional active agent is a B cell receptor pathway inhibitor. In some embodiments, the B cell receptor pathway inhibitor is a CD79A inhibitor, a CD79B inhibitor, an inhibitor. of CD 19, a Lyn inhibitor, a Syk inhibitor, a P13K inhibitor, a Blnk inhibitor, a PLCy inhibitor, a PKCP inhibitor, or a combination of these. In some embodiments, the at least one additional active agent is an antibody, a B cell receptor signaling inhibitor, a PI3K inhibitor, an IAP inhibitor, an mTOR inhibitor, a radioimmunotherapeutic, a DNA damaging agent. , a proteasome inhibitor, a histone deacetylase inhibitor, a protein kinase inhibitor, a hedgehog inhibitor, an Hsp90 inhibitor, a telomerase inhibitor, a Jakl/2 inhibitor, a protease inhibitor, a PKC inhibitor, a PARP inhibitor or a combination of these.

In one embodiment, the at least one additional active agent is an inhibitor of the checkpoint signaling pathway involving the programmed death receptor 1 (PD-1) and its ligands (PD-L1/2); one embodiment comprises a combination of an anti-PD-L1 agent and an anti-PD-1 agent. In one embodiment, the inhibitor is an anti-PD-L 1 agent selected from BMS-936559/MDx-1 105 (a fully human, high-affinity immunoglobulin (Ig) G4 monoclonal antibody against PD-L1), MPDL3280A (a modified human monoclonal antibody targeting PD-L 1), MSB0010718C and MEDI473. In one embodiment, the inhibitor is an anti-PD-1 agent selected from CT-011/pidilizumab, BMS-936558/MDX-1106/nivolumab and pembrolizumab. In one embodiment, the inhibitor is selected from BMS-936559/MDX-1105, MPDL3280A, MSB0010718C, MED1473, CT-011/pidilizumab BMS-936558/MDX-1106/nivolumab and pembrolizumab, and combinations of two or more of any of the previous. In one embodiment, the inhibitor is selected from the group consisting of ipilimumab, pembrolizumab, nivolumab, atezolizumab, avelumab, durvalumab and combinations thereof. In one embodiment, the inhibitor is an anti-CTLA-4 antibody. An example of an anti-CTLA-4 antibody is Ipilimumab (trade name Yervoy).

In one embodiment, the at least one additional active agent is a therapeutic agent selected from the group consisting of immunomodulatory drugs (IMids) that can stimulate both NK cells and T lymphocytes such as thalidomide, lenalidomide and pomalidomide. In one embodiment, the combination therapy also includes an inhibitory anti-KIR antibody (IPH-2102).

In one embodiment, the at least one additional active agent is a therapeutic agent selected from indoleamine-2,3-dioxygenase (IDO) inhibitors. In one embodiment, the inhibitor is selected from the group consisting of indoximod, INCB024360, ^N1G 919, IDO1 derived peptide, epacadostat, GDC0919 or a combination thereof. In one embodiment, the at least one additional active agent is a therapeutic agent selected from the group consisting of ibrutinib, rituximab, doxorubicin, prednisolone, vincristine, velcade and everolimus, and combinations thereof. In one embodiment, the at least one additional active agent is a therapeutic agent selected from cyclophosphamide, hydroxydaunorubicin (also called doxorubicin or Adriamycin™), vincristine (also called Oncovin™), prednisone, prednisolone and combinations thereof. In one embodiment, the at least one additional active agent is a therapeutic agent selected from the group consisting of BMS-936559/MDX-1105, MPDL3280A, MSB0010718C, MEDI473, CT-011/pidilizumab, BMS-936558/MDX-1106/nivolumab , and pembrolizumab, and combinations of two or more of any of the above.

In one embodiment, the at least one additional agent is selected from chlorambucil, ifosfamide, doxorubicin, mesalazine, thalidomide, lenlidomide, temsirolimus, everolimus, fludarabine, fostamatinib, paclitaxel, docetaxel, ofattumumab, rituximab, dexamethasone, prednisone, CAL-101, ibritumomab. , tositumomab, bortezomib, pentostatin, endostatin or a combination of these.

In one embodiment, the at least one additional active agent is a monoclonal antibody such as, for example, alemtuzumab, bevacizumab, catumaxomab, cetuximab, edrecolomab, gemtuzumab, ofatumumab, panitumumab, rituximab, trastuzumab, eculizumab, efalizumab,muromab-CB3, natalizumab. , adalimumab, afelimomab, certolizumab pegol, golimumab, infliximab, basiliximab, canakinumab, daclizumab, mepolizumab, tocilizumab, ustekinumab, ibritumomab tiuxetan, tositumoma, abagovomab, adecatumumab, alemtuzumab, anti-CD30 monoclonal antibody Xmab2513, anti-MET monoclonal antibody MetMab, a polizumab, apomab , arcitumomab, basiliximab, bispecific antibody 2B1, blinatumomab, brentuximab vedotin, capromab pendetide, cixutumumab, claudiximab, conatumumab, dacetuzumab, deno-sumab, eculizumab epratuzumab, ertumaxomab, etaracizumab, figitumumab, fresolimumab, galiximab, ganitumab, gemtuzumab ozogamic ina, glembatumumab, ibritumomab , inotuzumab ozogamicin, ipilimumab, lexatumumab, lintuzumab, lintuzumab, lucatumumab, Mapatumumab, Matuzumab, Milatuzumab, CC49 monoclonal antibody, Necitumumab, Nimotuzumab, Ofatumumab, Oregovomab, Pertuzumab, Ramacurimab, Ranibizumab, Siplizumab, Sonepci Zumab, Tane-Zumab, Tositumomab, Trastuzumab , tremelimumab, tucotuzumab celmoleukin, veltuzumab, visilizumab, volociximab and zalutumumab, rituximab, certuximab, daraumumab, ublituximab (TG-1101), ocaratuzumab (AME-133), obinutuzumab (GA-101).

In one embodiment, the at least one additional active agent is a cytokine selected from the group consisting of interferons (INF) and interleukins (IL). Examples of interferons include INF-alpha. Examples of interleukins include IL-2 (aldesleukin), IL-6, IL-12, IL-15, and IL-21.

In the context of combination therapy, administration of the dipivefrin composition may be simultaneous or sequential to the administration of one or more additional active agents. In another embodiment, the administration of the different components of a combination therapy can be carried out at different frequencies. The one or more additional active agents may be administered before (e.g., 5 minutes, 15 minutes, 30 minutes, 45 minutes, 1 hour, 2 hours, 4 hours, 6 hours, 12 hours, 24 hours, 48 hours, 72 hours , 96 hours, 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 8 weeks or 12 weeks before), concomitantly or subsequently (for example, 5 minutes, 15 minutes, 30 minutes, 45 minutes , 1 hour, 2 hours, 4 hours, 6 hours, 12 hours, 24 hours, 48 hours, 72 hours, 96 hours, 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 8 weeks or 12 weeks later) to the administration of a compound of the present description.

The one or more additional active agents may be formulated for co-administration with a dipivefrin composition in a single dosage form, as described in more detail herein. The one or more additional active agents may be administered separately from the dosage form comprising the compound of the present description. When the additional active agent is administered separately from the dipivefrin composition, it may be by the same or different route of administration as the dipivefrin composition.

Preferably, administration of a dipivefrin composition in combination with one or more additional active agents provides a synergistic response in the subject being treated. In this context, the term "synergistic" refers to the effectiveness of the combination being greater than that of the additive effects of either therapy alone. The synergistic effect of a combination therapy according to the description may allow the use of lower doses and/or less frequent administration of at least one active agent in the combination compared to its dose and/or frequency outside the combination . Additional beneficial effects of the combination may be manifested in avoiding or reducing adverse or unwanted side effects associated with the use of any one of the therapies in the combination administered alone (also called monotherapy).

The dosage form of the dipivefrin composition is an oral dosage form.

In one embodiment, the standard chemotherapy regimen comprises one or more therapeutic agents selected from the group consisting of ibrutinib, rituximab, doxorubicin, prednisolone, vincristine, velcade, cyclophosphamide, dexamethasone and everolimus. In one embodiment, the standard chemotherapy regimen is selected from CHOP (cyclophosphamide, hydroxydaunorubicin, Oncovin™ (vincristine) and prednisone or prednisolone), COOP (cyclofosamide, vincristine sulfate, prednisone), EPOCH (etoposide, prednisone, vincristine sulfate, cyclophosphamide, doxorubicin hydrochloride, Hyper-CVAD (cyclophosphamide, vincristine sulfate, doxorubicin hydrochloride, dexamethasone), ICE (ifosfamide, carboplatin, etoposide), R-CHOP (rituximab, cyclophosphamide, vincristine sulfate, procarbazine hydrochloride, prednisone and R-CVP (rituximab, cyclofosamide, vincristine sulfate, prednisone).

In one embodiment, the dipivefrin composition can be administered in combination with a chemotherapy regimen for the treatment of lymphoma. In one embodiment, the chemotherapy regimen is the CHOP regimen. In another embodiment, the chemotherapy regimen is selected from COOP, CVP, ^{eP or} CH, Hyper-CVAD, ICE, R-CHOP and R-CVP.

"Combination therapy" also encompasses administration of the compounds of the present disclosure in additional combination with non-pharmacological therapies (e.g., surgery or radiotherapy). When the combination therapy further comprises a non-pharmacological treatment, the non-pharmacological treatment may be performed at any suitable time as long as a beneficial effect is achieved from the joint action of the combination of the therapeutic compounds and the non-pharmacological treatment. For example, in appropriate cases, the beneficial effect is still achieved when the non-pharmacological treatment is temporarily withdrawn from the administration of the therapeutic compounds, perhaps for days or even weeks.

Non-pharmacological treatment can be selected from chemotherapy, radiotherapy, hormonal therapy, anti-estrogen therapy, gene therapy and surgery. For example, a non-drug therapy is removal of an ovary (for example, to reduce the level of estrogen in the body), thoracentesis (for example, to remove fluid from the chest), paracentesis (for example, to remove fluid from the abdomen ), surgery to remove or shrink angiomyolipomas, lung transplant (and optionally with an antibiotic to prevent infection due to the transplant), or oxygen therapy (for example, through a nasal cannula that contains two small plastic tubes or cannulas that are placed in both nostrils, through a mask that fits over the nose and mouth, or through a small tube that is inserted into the windpipe through the front of the neck, also called transtracheal oxygen therapy).

Treatment of microbial infection

The dipivefrin composition may be administered to a subject needing treatment of a microbial infection. The microbial infection can be a bacterial, viral, fungal or parasitic infection.

The bacterial infection may be a mycobacterial infection; a Gram positive bacterial infection, such as a Spirochete infection, Staphylococcus infection, Steptococcus infection, Clostridium infection, Vibrio infection, Bacillus infection, Salmonella infection, Listeria infection or Corynebacterium infection; or a Gram-negative bacterial infection, such as an E. coli infection, a Klebsiella pneumoniae infection, an Acinetobacter baumannii infection, a Pseudomonas aeruginosa infection, a Neisseria gonorrhoeae infection, or a Yersinia pestis infection, Neisseria infection meningitides. A Hemophilis influenzae B infection , Lyme disease spirochete infection, Mycobacterium leprae infection, Pneumococcus spp infection, Treponema pallidum infection, Legionella pneumophilia infection, Brucella abortus infection, Mycobacterium tuberculosis infection, Mycoplasma infection. Bacillus anthracis, Streptococcus agalactiae, Streptococcus pyogenes, Escherichia coli, Neisseria gonorrhoeae, Neisseria meningitides or Pseudomonas aeruginosa.

Viral infection may include influenza, a herpes virus infection, a dengue virus infection, a human immunodeficiency virus infection, a hepatitis virus infection, a West Nile virus infection, a cytomegalovirus infection , a rabies virus infection, a flavivirus infection, a rhinovirus infection, a papillomavirus infection, a paramyxovirus infection, a parainfluenza virus infection, a retrovirus infection, or an infection caused by the following viruses: Sendai virus, feline leukemia virus, Reo virus, poliovirus, human serum parvovirus-like virus, simian virus 40, respiratory syncytial virus, mouse mammary tumor virus, varicella-zoster virus , dengue virus, rubella virus, measles virus, adenovirus, human T-cell leukemia virus, Epstein-Barr virus, murine leukemia virus, mumps virus, vesicular stomatitis virus, Sindbis virus, lymphocytic choriomeningitis virus or bluetongue virus.

Fungal infection can be a yeast infection or a filamentous fungal infection. Examples of a fungal infection include systemic candidiasis, aspergillosis, cryptococcosis, blastomycosis, coccidioidomycosis, histoplasmosis and mucormycosis , Microsporum, Trichophyton, Epidermophyton, Sporothrix schenckii, Cryptococcus neoformans, Coccidioides immitis, Histoplasma capsulatum, Blastomyces dermatitidis or Candida albican.

Parasitic infection may include malaria and an endoparasitic infection by helminths or filarial nematodes, acanthamoeba infection, acanthamoeba infection keratitis, African sleeping sickness, alveolar echinococcosis, amoebiasis, American trypanosomiasis, hookworm, angiostrongyliasis, anisakiasis, ascariasis, babesiosis, balantidiasis , balamutia, baylisascariasis, bed bugs, biharzia, Blastocystis hominis infection, body lice infestation, Capilariasis, cercarial dermatitis, Chagas disease, chilomastix mesnili infection, clonorchiasis, CLM, "Crabs", cryptosporidiosis, cutaneous lava migrans, cyclosporiasis, cysticercosis, cystoisospora infection, dientamoeba fragilis, diphyllobothriasis, dipylidium caninum infection, dirofilariasis ( heartworm infection), DPDx, dracunculiasis, dog tapeworm, echinococcosis, elephantiasis, entamoeba histolytica infection, entamoeba polecki, enterobiasis, fascioliasis, fasciolopsiasis, filariasis , giardiasis, gnathostomiasis, guinea worm disease, lice infestation, heterophyasis, hookworm, hydatid disease, hymenolepiasis, intestinal worms , Iodamoeba buetschlii infection, isospora infection, visceral leishmaniasis, keratitis, leishmaniasis, loiasis, lymphatic filariasis, malaria, microsporidiosis, mite infestation, myiasis , Naegleria infection, neurocysticercosis, neglected parasitic infections in the United States, neglected tropical disease, ocular larva migrans, onchocerciasis, opisthorchiasis, paragonimiasis, pediculosis, ptyriasis, pinworm infection, Plasmodium infection, pneumonia pneumocystis jirovecii, pseudonewfoundland infection, pubic lice infestation, raccoon roundworm infection, river blindness, sappinia, sarcocystosis, scabies, schistosomiasis, sleeping sickness, soil-transmitted helminths, strongyloidiasis, swimmer's itch, taeniasis, infection for tapeworm, toxocariasis, trichinellosis, trichinellosis, trichomoniasis, trichuriasis, trypanosomiasis, visceral larva migrans, waterborne disease, whipworm infection, zoonotic disease or zoonotic helminth infection.

The treatment of the microbial infection may further be a combination therapy comprising the administration of dipivefrin and at least one or more additional chemotherapy treatments that exert a direct inhibitory effect against the microbial pathogen in the subject, referred to herein as "antimicrobial agent." ". The antimicrobial agent may be an antibiotic, an antifungal agent, an antiviral agent, an antiparasitic agent or a combination of these.

Examples of antibiotics include a beta-lactam antibiotic, a tetracycline, a sulfonamide antibiotic, an aminoglycoside antibiotic, a macrolide antibiotic, a fluoroquinolone, and a quinolone antibiotic. Examples of a beta-lactam antibiotic include a cephalosporin, a penicillin, a monobactam, a carbapenem, and a carbacefem. Examples of aminoglycoside antibiotics include streptomycin, dihydrostreptomycin, amikacin, apramycin, arbekacin, astromycin, bekanamycin, dibekacin, framycetin, gentamicin, hygromycin B, isepamycin, kanamycin, neomycin, netilmycin, paromomycin, rhodostreptomycin, ribostamycin, sisomicin, spectinomycin, tobramycin, and verdamycin. Examples of a fluoroquinolone include ciprofloxacin, clinafloxacin, enoxacin, fleroxacin, gatifloxacin, moxifloxacin, gemifloxacin, grepafloxacin, levofloxacin, norfloxacin, sparfloxacin and trovafloxacin. Examples of a quinolone include cinoxacin, garenoxacin and nalidixic acid. Examples of a macrolide include azithromycin, clarithromycin, dirithromycin, erythromycin, lincomycin, roxithromycin, troleandomycin, telithromycin and spectinomycin. Examples of a tetracycline include demeclocycline, doxycycline, minocycline, oxytetracycline, tgecycline and tetracycline. Examples of a sulfonamide antibiotic include Sulfamethizole, Sulfamethoxazole, Sulfisoxazole, Trimethoprim-Sulfamethoxazole.

Examples of antifungal agents include amphotericin B, candicidin, filipin, hamicin, natamycin, nystatin, rimocidin, bifonazole, butoconazole, clotrimazole, econazole, fenticonazole, isoconazole, ketoconazole, luliconazole, miconazole, omoconazole, oxiconazole, sertaconazole, sulconazole, tioconazole, albaconazole , efinaconazole, epoxiconazole, fluconazole, isavuconazole, itraconazole, posaconazole, propiconazole, ravuconazole, terconazole, voriconazole, abafungin, allylamines, anidulafungin, caspofungin, micafungin, aurones, benzoic acid, cyclopirox, flucytosine, griseofulvin, haloprogin, tolnaftate, undecitic acid, crystal violet and balsam of Peru.

Examples of an antiviral agent useful in the treatment of viral infections such as influenza include neuraminidase inhibitors (e.g., oseltamivir and zanamivir) and M2 ion channel inhibitors (e.g., amantadine and rimantadine) and agents that inhibit replication. viral infection, transcription, reverse transcription or the production of viral particles. In one embodiment, the antiviral agent is selected from the group consisting of (+)-calanolide A; (+)-dihydrocalanolide A; 145U87; 2'-C-methyl-7-deazaadenosine;2'-C-methylcytidine; 2-nor-cyclic GMP; 3,4-dicaffeoylquinic acid; 3-hydroxymethyl dicamphanoyl khelactone; 3-hydroxyphthaloyl-beta-lactoglobulin; 3-nitrosobenzamide; 4-azidothymidine; 4-methyl dicamphanoyl kelactone; 524C79; 739W94; A 160621; A 315675; A 315677; A 5021, A 74259; A 7704; A 77003; A 80735; A 80987; A 91883A; A 98881; A-837093; abacavir; AC 2; acemannanl acetylcysteine-zambon; ACH 126445; ACH 126447; acyclovir (e.g., extended-release, controlled-release, topical patch); acyclovir-PMPA; ACP HIP; actinohivine; AD 439; AD 519; adamantylamide dipeptide; adefovir (for example, dipivoxil); ADS 11; afovirsen; AG 1284; AG 1350; GA 1478; AG 1859; GA 555; AG 6840; AG 6863; ^to G-021541; AGT-1; AHA 008; aidfarel; AL 721; alamifovir; albuferon; albumin/interferon-alpha; aldesleukin; ALN RSV01; alovudine; HGA alpha; alpha-IPDX; alpha-antitrypsin; alvircept sudotox; alvocidib; ALX 0019; ALX404C; AM 285; AM 365; amantadine; AMD 070; AMD 3329; AMD 3465; AMD 8664; amdoxovir; amidinomycin; aminopeptidase; amitivir; ampligen; amprenavir; AMZ 0026; ANA 971; ANA 975; ancriviroc; andrographis; anti-CCR5 monoclonal antibody; sheep anti-CCR5/CXCR4 monoclonal antibody; anti-CD3 CD4IgG monoclonal antibody conjugate; anti-CD4 monoclonal antibody; anti-CD7 monoclonal antibody; anti-CD8 monoclonal antibody; anti-CMV monoclonal antibody; anti-hepatitis B ribozyme; anti-HIV catalytic antibody; anti-HIV immunotoxin (IVAX); human monoclonal anti-HIV-1; 2FS antibody; human monoclonal anti-HIV-1; 2G12 antibody; human monoclonal anti-HIV-1; 4E10 antibody; antineoplaston AS2 1 (eg, oral); Anti-RSV antibody (Intracel, Corp.); PB2 antisense oligonucleotide; AUG; Aop-RANTES; aphidicolin; aplaviroc; apricitabine; AQ 148; A ^r 132; AR 177; ARB 95214; ARB 97265; ARB 97268; arbidol; ARQ 323; artemether; atermisinin; artesunate; AS 101; AT 61; atazanavir; atevirdine; atorvastatin; AV 1101; AV 2921; AV 2923; AV 2925; AV 2927; avarol; AVI 4065; AVR 118; AXD 455; azidodideoxyguanosine; azodicarbonamide; bafilomycin A1; baicalin; bavituximab; BAY 414109; BAY 439695; BAY 504798; BAY Z 4305; BB 10010; BB2116; BCH 10652; BCH 371; BCH 527; BCTP; BCX 140; BCX 1591; BCX 1827; BCX 1898; BCX 1923; BEA; BEA 005; belenamina; benanomycin A; benzalkonium (eg chloride); benzalkonium chloride/octoxinol 9 (e.g. vaginal gel); beta-D-FDOC; Beta-L-ddC; beta-L-FddC; bevirimat; BG 777; BGP 15; BILA2185 BS; BILN 303 SE; BILR 355; BIRM ECA 10-142; BIVN 401; BL 1743; BLX 833 (e.g., controlled release); BM 510836; BMS 181167-02; BMS 181184; BMS 182193; BMS 186318; BMS 187071; BMS 488043; BMS 806; BMY 27709; boceprevir (SCH 503034); brecanavir; brefeldin A; brequinar; brivudine; BRL 47923DP; BSL 4; BST 500L; BTA 188; BTA 798; C 1605; C 2507; C31G; calcium spirulan; canventol; capravirin; carbendazim; carbocyclic deazaadenosine; carbopol polymer gel; carbovir; CC 3052; CD4 fusion toxin; CD4 IgG; CD4-ricin A chain; celgosivir; cellcept; cellulose sulfate; cepharantin; brush; CF 1743; CFY 196; CGA 137053; CGP 35269; CGP 49689; CGP 53437; CGP 53820; CGP 57813; CGP 61783; CGP 64222; CGP 70726; CGP 75136; CGP 75176; CGP 75355; chloroquine (eg phosphate); CI 1012; CI 1013; cidofovir; ciluprevir (BILN 2061); civacir; civamide; CL 190038; CL 387626; clevudine; CMV 423; CMX 001; CNBA-Na; NCJ 102; cobra venom peptide; Colloidal Silver; conocurvone; Cossala; costatolide; CP 1018161; CP 38; PC 51; CPFDD; CpG 10101; CRL 1072; crofelemer; C.S. 8958; CS 92; CT 2576; CTC 96; curcumin; curdlan sulfate; cyanovirin-N; cyclosporine; CYT 99007; cytarabine; cytomegalovirus immunoglobulin; DAB486interleukin-2; DABO 1220; dacopafant; DAP 30; DAP 32; dapivirine; darunavir; D-aspartic-betahydroxamate; DB 340; DDCDP-DG; DDGA; deazaadenosine; deazzaneplanocin A; DEB 025; DEBIO-025; delavirdine; delimited; denileukin diftitox; deoxyfluoroguanosine; DES 6; dexel-vucitabine; dextran sulfate; dextrin 2-sulfate; DG 35; didanosine; dideoxyadenosine; dideoxyguanosine; dideoxythymidine; didox; dihydroartemisinin; dihydrocostatolide; dinitrochlorobenzene; LD 110; DMP 323; MPD 850; DMP 851; DmTr-ODN12; docosanol; DP 107; DPC 082; DPC 083; DPC 681; DPC 684; DPC 961; DPC 963; droxinavir; DUP 925; DYE; E 913; EB-foscamet; edodequin alfa; edoxudin; E-EPSEU; efavirenz; EGS 21; EHC 18; EHT 899; elvucitabine; EM 1421; EM 2487; emivirine; emtricitabine; emtricitabine/tenofovir disoproxil fumarate; ZEM 702; enfuvirtida; entecavir; eosinophil-derived neutralizing agent; episiastatin B; ET 007; etanercept; ether lipid analogue; etoviram; etravirine; F 105; F 36; F50003; famciclovir; fas ligand inhibitor; fasudil; fattivirazine A1; FEAU; feglimycin; felvizumab; FGI 345; fiacitabine; fialuridine; FLG; floxuridine; flutimide; fluvastatin (eg sodium); fornivirsen; fosalvudine tidoxil; fosamprenavir; foscarnet sodium; fozivudine; FP 21399; F-PBT; Fp MpA; FPMPDAP; FR 191512; FR 198248; galactan sulfate; ganciclovir; GAP 31; GCA 186; GCPK; GE 20372A; GE 20372B; GEM 122; GEM 132; GEM 144; GEM 92; GEM 93; gemcitabine (eg hydrochloride); ginseng; glamolec; glutathionearsenoxide; glucovir; glycyrrhizin; GMDP; GO 6976; GO 7716; GO 7775; Gossypol; GPG-NH2; GPI 1485; GPI 2A; GPs 0193; GR 137615; GR 137615; GR 92938X; G.S. 2838; G.S. 2992; G.S. 3333; G.S. 3435; G.S. 4071; GS 438; G.S. 7340; GS 9005; G.S. 9132; GS 9160; GS 930; GW 275175; GW5950X; HB 19; HBT 946; HCV 086; HCV 371; HCV AB 68; HCV-796; HCV-SM; HE 2000; HE 317; hepatitis B immunoglobulin; hepatitis C immunoglobulin; hepex C; HEPT; heptazyme; HGS-H/A27; HI 236; HI 240; HI 244; HI 280; HI 346; HI 443; HI 445; histamine; histamine dihydrochloride (eg, injection, oral); HIV DNA vaccine (Antigen Express, Inc.); HIV immunoglobulin; HIV immune plasma; HL 9; HOE Ba Y 793; HRG 214; HS 058; huMax-HepC; hydroxycarbamide; hydroxychloroquine; hypericin; 152; IAZT; CIE 17261; IDN 6556; idoxuridine; IM28; imiquimod; immStat; immuDyn; immunocal; imreg 1; incadronic acid; INCB 9471; indinavir; infliximab; Zn2+ finger peptide from influenza matrix protein; ingenol triacetate; inophil B; inosine pranohex; interferon; interferon alfa-2a; interferon alfa-2b (eg, inhalation); interferon alfacon-1; alpha interferon (e.g., sustained release, intranasal, omniferon); interferon alfa-2b (e.g., controlled release or transdermal); interferon alfa-2b gene therapy; alpha-n3 interferon; interferon beta-1a; interferon beta-1b; interferon gamma-1b; omega interferon; interferon-tau; interleukin 10 (eg, human recombinant); interleukin-1 type I receptor; interleukin-13; interleukin-15; interleukin-16; interleukin-2 agonist; interleukin-4; IPdR: ipilimumab; isatoribine; ISIS 13312; ISIS 14803; ISO ddA; ITI 002; ITI 011; ITMN-191; JBP 485; JCA 304; JE 2147; JM 1596; JM 2763; JTK 003; JTK 109; JTK 303; K12; K 37; K 42; ketoxal kamizole; kijimycin; kistamycin; KKKI 538; KM 043; KNI 102; KNI 241; KNI 272; KNI 413; KNI 684; kootikuppala; KP 1461; KPC 2; KPE 00001113; KPE 02003002; KRH 1120; L 689502; L 693549; L 696229; L 696474; L 696661; L 697639; L 697661; L 708906; L 731988; L 732801; L 734005; L 735882; L 738372; L 738684; L 738872; L 739594; L 748496; L 754394; L 756423; L 870810; L HAS ara AMP; lactoferrin; lamivudine; lamivudine/abacavir; lamivudine/zidovudine; lamivudine/zidovudine/abacavir; lasinavir; LB 71116; LB 71148; LB 71262; LB 71350; LB 80380; LB 84451; L-chicoric acid; lecithinated superoxide dismutase; leflunomide; lentinan; leukocyte interleukin injection (CEL-SCI Corp.); leukotriene B4-LTB4; levcycloserine; levofloxacin; lexithromycin; licorice root; Liposomal ODG-PFA-OMe; lithium succinate; lobucavir; lodenosine; lopinavir; lovastatin; lovirida; lufironil; LY 180299; LY 214624; LY 253963; LY 289612; LY 296242; LY 296416; LY 309391; LY 309840; LY 3111912; LY 314163; LY 314177; LY 316683; LY 326188; LY 326594; LY 326620; LY 338387; LY 343804; LY 354400; LY 355455; LY 366094; LY 366405; LY 368177; LY 73497; lysozyme; M 40401; M4N; Madú; mannan sulfate; MAP 30; maraviroe; maribavir; masoprocol; MB-focarnet; MC 207044; MC 207044; MC 207685; MC 867 mCDS71; MDI-P; MDL 101028; MDL 20610; MDL 27393; MDL 73660; MDL 74428; MDL 74695; MDL 74968; MDX240; ME 3738; ME 609; MEDI 488; Medusa interferon; MENU 10690; MEN 10979; MERN5075A; Merimepodib (VX-497); metenkephalin; methazone; mevastatin; MGN 3; michelamine B; miglustat; milk thistle; mitoquinone; MIV 150; MIV 210; mivotylate; MK 0518; MK 944A; MM 1; MMS 1; MOL 0275; monoclonal antibody 1F7; monoclonal antibody 2F5; monoclonal antibody 3F12; monoclonal antibody 447-52D; monoclonal antibody 50-61A; B4 monoclonal antibody; HNK20 monoclonal antibody; monoclonal antibody NM01; mopiridone; moroxidine; motavizumab; motexafin gadolinium; mozenavir; MPC 531; MRK 1; Ms 1060; MS 1126; MS 8209; MS 888; MSC 127; MSH 143; MTCH 2; MTP-PE; murabutide; MV 026048; MX 313; mycophenolate mofetil; mycophenotic acid; navuridine; NB 001; Nalfinavir (e.g. mesylate); neomycin B-arginine conjugate; neotripterifordin; nevirapine; NIM 811; nitazoxanide; nitric oxide (e.g. ProStrakan); nitrodeazauridine; NM 01; NM 49; NM 55; N-nonyl-DNJ; NNY-RANTES; nonacin; NOV 205; NP 06; NP 77A; NPC 15437; NSC 158393; NSC 158393; NSC 20625; NS 287474; NSC 4493; NSC 615985; NSC 620055; NSC 624151; NSC 624321; NSC 627708; NSC 651016; NSC 667952; NSC 708199; NV 01; NV-08; Octoxynol 9; OCX 0191; OH1; OKU 40; OKU 41; oltipraz; omacyclovir; opaviralin; OPT TL3; oragen; ORI 9020; oseltamivir; oxetanocin; oxothiazolidine carboxylate; P 56; PA 344/PA 344B; palinavir; palivizumab; PAMBAEEG; papuamide A; PBS 119; PC 1250; PC 515; PCL 016; PD 0084430; PD 144795; PD 153103; PD 157945; PD 169277; PD 171277; PD 171791; PD 173606; PD 173638; PD 177298; PD 178390; PD 178392; PD 190497; pegaldesleukin; peginterferon alfa-2a; peginterferon alfa-2b; PEGinterferon alfacon-1; pegylated interferon; pegylated thymalphasin; peldesin; PEN 203; penciclovir; pentosan polysulfate; pentoxifylline; T peptide; peramivir; PETT 4; PF-03491390; PG 301029; PG 36; phellodendrine; phosphatidylamivudine; phosphatidylzalcitabine; phosphatidylzidovudine; phosphacide; phosphinic cyclocreatine; pinosylvina; pyrodavir; PL 2500; pleconaryl; plerixafor; MP 104; PM 19; PM 523; PM 92131; PM94006; PEDAP; PMS 601; PMTG; PMTI; PN 355; PNU 103657; PNU 142721; podophyllotoxin; poly ICLC; polyadenylic polyuridylic acid; polysaccharide K; PP 29; PPB 2; PPL 100; pradefovir; Pradimycin A; prasterone; PRO 140; PRO 2000; PRO 367; PRO 542; probucol (Vyrex Corp.); propagermanium; prostratin; pseudohypericin; PSI 5004; PSI-6130; PTPR; PTX 111; pyriferone; Q 8045; QM 96521; QM 96639; AR 435; quinben; quinxapeptin A; quinoxapeptin B; QYL-438; QYL-609; QYL-685; QYL-769; R 1518; R 1626; R 170591; R 18893; R 61837; R 71762; R803; R82150; R82913; R851; R87366; R 91767; R 944; R95288; R-1626; R7128; raluridine; ramatroban; ranpirnase; RB 2121; RBC CD4; RD 30028; RD 42024; RD 42138; RD 42217; RD 42227; RD 62198; RD 65071; RD6 Y664; regavirumab; resiquimod; resobeno; respiratory syncytial virus immunoglobulin; retrogen; REV 123; RFI 641; ribavirin; rilpivirine; rimantadine; ritonavir; RKS 1443; RO 0334649; RO 247429; RO 250236; RO 316840; RO 54445; robustaflavone; rolipram; rosiglitazone; RP 70034; RP 71955; RPI 312; RPI 856; RPR 103611; RPR 106868; RPR 111423; RS 654; RS 980; RSV 604; rubitecan; rupintrivir; S 1360; S 2720; S 9a; HS 1042; HS 8443; saquinavir (e.g. mesylate); sargramostim; S 180922; SB 205700; SB 206343; SB 73; SC 49483; SC 55099; SCH 350634; SCH 6; schisandra; SCV 07; SCY-635; SD 894; S-DABO; SDF 1; SDZ 282870; SDZ 283053; SDZ 283471; SDZ 89104; SDZ PRI 053; SE 063; semapimod; sevirumab; SF950; SF 953; siamycin 1; siamycin 2; sICAM-1; sifuvirtida; FOLLOW 246; silipid, simvastatin; simvastatin hydroxyl acid, ammonium salt; sizofiran; SJ 3366; SK 034; SKF 108922; SKI 1695; SO 324; sodium lauryl sulfate; solutein; sorivudin (eg, tropical); SP 10; SP 1093V; sparphosic acid; SPC 3; SPD 756; specifEx-Hep B; SPI 119; SPL 2992; SPL 7013; SPV 30; SR 10204; SR 10208; SR 11335; SR 3745A; SR 3773; SR 3775; SR 3784; SR 3785; SR 3785; SR 41476; SRL 172; SRR SB3; ST 135647; stalimycin stachifline; stampidine; statolon; stavudine; steponin; suksdorphin; sulfated maltoheptaose; superoxide dismutase; suramin (e.g. sodium); Sy 801; T1100; T 118; T 22; T 30695; T 611; T 705; T4GEN; tacrine; TAK 220; TAK 652; TAK 779; talviralin; TAP 29; taribavarin; TASP; tecleukin; tecogalan (eg sodium); TEI 2306; telaprevir (VX950); telbivudine; telinavir; temacrazine; tenidap; tenofovir; tenofovir disoproxil fumarate; TGG II 23A; TH 9407; TH 9411; thalidomide; thiophosphonoformic acid; thiovir; thymalfasine (for example, zadaxin); timoctonane; thymosin fraction 5; timotrinan; thymus extract; tICAM-1; tifuvirtide; tilarginine; tipranavir; tivicyclovir; tivirapine; TJ 41; TJ 9; TL 3024; TMC 126; TNF-alpha inhibitor; TNK 6123; TNX 355; todoxin; TOFA; tomeglovir; transforming growth factor-alpha; TraT; trecovirsen; tremacamra; trichosanthin; triciribine; trichonal; trifluridine; trimidox; trodusquemine; tromantadine; trovirdine; tucaresol; tunicamycin; tuvirumab; U 103017; U75875; U78036; U80493; U81749; U88204E; U96988; U 9843; UA 926; Ubenimex; UC 10; UC 16; UC 38; UC 42; UC 68; UC 70; UC 781; UC 81; UC 82; UIC 94003; Ukraine; UL36ANTI; UMJD 828; ursodeoxycholic acid; UT 231B; valacyclovir; valganciclovir; valopicitabine (NM 238); valopicitabine (NM-238); valtorcitabine; varicella zoster immunoglobulin; VB 19038; vesnarinone; VF 1634; v Gv 1; VGX 410; vicriviroc; vidarabine; vincristine (e.g. sulfate); VIR 101; viraprexin; virodenum; virostat; viscum album extract; VP 50406; VRT 21493; VRX 496; vX 10166; vX 10217; VX 10493; VX 11106; WF 10; WHI 05; WHI 07; WIN 49569; WIN 49611; WM 5; WR 151327; XK 216; XK 234; XN 482; XP 951; XQ 9302; XR 835; XTL 2125; XTL 6865; XU 348; XU 430; Y-ART-3; YHI 1; YK FH312; Z 100; Z 15; zalcitabine; zanamivir; zidovudine (eg, phosphate-didanosine dimer); zidovudine triphosphate mimetics; ZX0610; ZX0620; ZX0791; ZX0792; ZX 0793; ZX0851; ZY II, and combinations of these.

In one embodiment, the antiviral agent is selected from the group consisting of abacavir, acyclovir (acyclovir), adefovir, amantadine, amprenavir (agenerase), ampligen, arbidol, atazanavir, atripla, balavir, idofovir, combivir, dolutegravir, darunavir, delavirdine, didanosine, docosanol, edoxudine, efavirenz, emtricitabine, enfuvirtide, entecavir, ecoliever, famciclovir, fixed-dose combination (antiretroviral), fomivirsen, fosamprenavir, foscarnet, fosfonet, fusion inhibitor, ganciclovir, ibacitabine, imunovir, idoxuridine, imiquimod, indinavir , inosine, integrase inhibitor, type III interferon, type II interferon, type I interferon, interferon, lamivudine, lopinavir, loviride, maraviroc, moroxidine, metisazone, nelfinavir, nevirapine, nexavir, nitazoxanide, nucleoside analogues, novir, oseltamivir, peginterferon alfa-2a, Penciclovir, peramivir, pleconaril, podophyllotoxin, protease inhibitor, raltegravir, reverse transcriptase inhibitor, ribavirin, rimantadine, ritonavir, pyramidine, saquinavir, sofosbuvir, stavudine, synergistic enhancer (antiretroviral), telaprevir, tenofovir, tenofovir disoproxil, tipranavir, trifluridine, trizivir, tromantadine, truvada, valacyclovir (valtrex), valganciclovir, vicriviroc, vidarabine, viramidine, zalcitabine, zanamivir (relenza), zidovudine, and combinations of these.

Examples of antiparasitic agents include bephenium, diethylcarbamazine, ivermectin, niclosamide, piperazine, praziquantel, pyrantel, pyrvinium, albendazole, flubendazole, mebendazole, thiabendazole, benzyl benzoate, benzyl benzoate/disulfiram, lindane, malathion, permethrin, benzyl alcohol, butoxide of piperonyl/pyrethrins, spinosad and crotamiton.

Dipivephrine may be the free base or a pharmaceutically acceptable salt thereof. Preferably, the dipivefrin salt is an acid addition salt, for example dipivefrin hydrochloride. The dipivephrine may be racemic dipivephrine or optically purified D- or L-dipivephrine, preferably L-dipivephrine.

Additionally, dipivefrin can be isotopically labeled with a pharmaceutically acceptable isotopic label. Examples of isotopes suitable for inclusion in isotope-labeled dipivefrin, or a salt or derivative thereof, include hydrogen isotopes, such as 2H and 3H; carbon, such as 11C, 13C and 14C, chlorine, such as 36Cl; nitrogen, such as 13N and 15N; and oxygen, such as 15O, 17O and 18O. Isotope-labeled dipivefrin can be prepared by conventional techniques known to those skilled in the art.

Certain isotope-labeled dipivephrines, for example, those that incorporate a radioactive isotope, are useful in tissue distribution studies of drugs and/or substrates. The radioactive isotopes tritium, i.e. 3H, and carbon-14, i.e. 14C, are particularly useful for this purpose in view of their ease of incorporation and means of rapid detection. Substitution with heavier isotopes such as deuterium, i.e. 2H, may provide certain therapeutic advantages resulting from greater metabolic stability, for example, longer in vivo half-life or lower dosage requirements, and therefore may preferred in some circumstances. Substitution with positron-emitting isotopes, such as 11C, 18F, 15O, and 13N, may be useful in positron emission topography (PET) studies to examine receptor occupancy by substrate.

Also described is a composition comprising dipivephrine or one of its pharmaceutically acceptable salts, solvates, clathrates, polymorphs, analogues, prodrugs or derivatives. The composition may be suitable for pharmaceutical use and may be in the form of a pharmaceutical composition. The pharmaceutical composition may have any suitable form and may be a tablet, capsule, lyophilized solid, solution, suspension or a combination of these. The pharmaceutical composition may be an intravenous, injectable, topical or oral dosage form. The pharmaceutical composition may be a dosage form intended for parenteral administration, such as a lyophilized solid requiring reconstitution prior to administration or a reconstituted solution of the lyophilized solid. The pharmaceutical composition may be an oral dosage form in tablet or capsule form. In a preferred embodiment, dipivefrin is formulated in any oral dosage form including solid, semisolid, liquid, powder, sachet and the like. Solid oral dosage forms may include, for example, a tablet, capsule (hard or soft) or subunits and the like. "Subunit" includes a minitablet, a bead, a spheroid, a microsphere, a seed, a granule, a capsule, a microcapsule, a particle and the like that may provide an oral dosage form alone or when combined with other subunits. Illustrative semisolid or liquid dosage forms include a suspension, a solution, an emulsion, and the like. Solid oral dosage forms may also include oral dissolving/disintegrating (ODT) dosage forms. Examples of ODTs include orally dissolving/disintegrating tablets, orally dissolving films, and dosage forms intended for sublingual/lingual/buccal administration such as rapidly dissolving/disintegrating sublingual tablets and films.

The oral dosage form may be formulated for a specific type of release including immediate release, controlled release, sustained release, or prolonged release.

The dipivefrin composition is generally present within a pharmaceutical composition in a therapeutically effective amount. As used herein, a "therapeutically effective amount" is an amount that, upon administration to a patient, results in a perceptible benefit to the patient. An effective amount of a dipivefrin composition may be in the range of about 0.001 mg/kg to about 1000 mg/kg, about 0.01 mg/kg to about 100 mg/kg, about 10 mg/kg to about 250 mg/kg. kg, about 0.1 mg/kg to about 15 mg/kg; or any range in which the lower end of the range is any amount between 0.001 mg/g and 900 mg/kg and the upper end of the range is any amount between 0.1 mg/kg and 1000 mg/kg (for example, 0.005 mg /kg and 200 mg/kg, 0.5 mg/kg and 20 mg/kg). Effective doses will also vary, as recognized by those skilled in the art, depending on the diseases treated, the route of administration, the use of excipients and the possibility of joint use with other therapeutic treatments, such as the use of other agents.

Pharmaceutical compositions can be prepared by a process comprising combining dipivefrin with a pharmaceutically acceptable excipient. Excipients can be added to facilitate manufacturing, improve stability, improve product characteristics, improve bioavailability, improve patient acceptability, etc. Pharmaceutical excipients include carriers, fillers, binders, disintegrants, lubricants, glidants, granulating agents, compression aids, colorants, sweeteners, preservatives, suspending agents, dispersing agents, film formers, flavorings, printing dyes, buffering agents, pH adjusters, flavor masking agents, etc. In some cases, a single material will meet two or more of the general classifications above.

Also described is a combination pharmaceutical composition comprising a dipivephrine and at least one other active agent and at least one pharmaceutical excipient.

Therapeutically effective amounts of the compounds described herein may be administered to a mammal having a disease, disorder or condition to be treated as described herein. In some embodiments, the mammal is a human. Therapeutically effective amounts of the compounds may vary depending on the compounds, the severity of the disease, the age and relative health of the subject, and other factors.

The term "combination", as used herein, means a product that results from the mixture or combination of dipivefrin and any additional therapeutic agent and includes both fixed and non-fixed combinations. The term "fixed combination" means that dipivephrine and additional therapeutic agents are administered in a single entity or dosage form. The term "non-fixed combination" means that dipivephrine and additional therapeutic agents are administered as separate entities or dosage forms, either simultaneously, concurrently or sequentially, without specific intermediate time limits, wherein such administration provides therapeutic levels. effectiveness of the two compounds in the patient's body. The latter also applies to cocktail therapy, for example the administration of three or more active ingredients.

In some embodiments, the pharmaceutical combination and/or composition described herein also includes one or more pH adjusting agents or buffering agents, including acids such as acetic, boric, citric, lactic, phosphoric and hydrochloric acids; bases such as sodium hydroxide, sodium phosphate, sodium borate, sodium citrate, sodium acetate, sodium lactate and tris-hydroxymethylaminomethane; and buffers such as citrate/dextrose, sodium bicarbonate, and ammonium chloride. Said acids, bases and buffers are included in the amount necessary to maintain the pH of the composition in an acceptable range.

In some embodiments, the pharmaceutical combination and/or compositions also include one or more salts in an amount required to bring the osmolality of the composition to an acceptable range. Such salts include those that have sodium, potassium or ammonium cations and chloride, citrate, ascorbate, borate, phosphate, bicarbonate, sulfate, thiosulfate or bisulfite anions; Suitable salts include sodium chloride, potassium chloride, sodium thiosulfate, sodium bisulfite and ammonium sulfate.

The pharmaceutical formulations described herein are administered to a subject orally. The pharmaceutical formulations described herein include, but are not limited to, aqueous liquid dispersions, self-emulsifying dispersions, solid solutions, liposomal dispersions, aerosols, solid dosage forms, powders, immediate release formulations, controlled release formulations, fast melting formulations, tablets, capsules, pills, delayed release formulations, extended release formulations, pulsatile release formulations, multiparticle formulations and mixed immediate and controlled release formulations.

In some embodiments, pharmaceutical combinations and/or compositions that include a compound described herein are manufactured in a conventional manner, such as, by way of example only, by mixing, dissolving, granulating, drageing, levigation, conventional emulsification, encapsulation, entrapment or compression.

"Antifoam agents" reduce foaming during processing, which can cause coagulation of aqueous dispersions, bubbles in the finished film, or generally impair processing. Examples of antifoaming agents include silicon emulsions or sorbitan sesquoleate. "Antioxidants" include, for example, butylated hydroxytoluene (BHT), sodium ascorbate, ascorbic acid, sodium metabisulfite and tocopherol. In certain embodiments, antioxidants improve chemical stability when required.

In some embodiments, the compositions provided herein also include one or more preservatives to inhibit microbial activity. Suitable preservatives include mercury-containing substances such as merfen and thiomersal; stabilized chlorine dioxide; and quaternary ammonium compounds such as benzalkonium chloride, cetyltrimethylammonium bromide, cetylpyridinium chloride and parabens.

In some embodiments, the formulations described herein benefit from antioxidants, metal chelating agents, thiol-containing compounds and other general stabilizing agents. Examples of such stabilizing agents include, but are not limited to: (a) about 0.5% to about 2% w/v glycerol, (b) about 0.1% to about 1% w/v methionine, (c) about 0.1% to about 2% w/v monothioglycerol, (d) about 1 mm to about 10 mm EDTA, € about 0.01% to about 2% w/v ascorbic acid, (f ) 0.003% to about 0.02% w/v polysorbate 80, (g) 0.001% to about 0.05% w/v polysorbate 20, (h) arginine, (i) heparin, (j) dextran sulfate , (k) cyclodextrins, (l) pentosan polysulfate and other heparinoids, (m) cyclodextrins, (l) pentosan polysulfate and other heparinoids, (m) divalent cations such as magnesium and zinc; or (n) combinations of these.

"Binders" impart cohesive qualities and include, for example, alginic acid and salts thereof; cellulose derivatives such as carboxymethylcellulose, methylcellulose (e.g., Methocel®), hydroxypropylmethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose (e.g., Klucel®), ethylcellulose (e.g., Ethocel®) and microcrystalline cellulose (e.g., Avicel®); microcrystalline dextrose; amylose; magnesium aluminum silicate: polysaccharide acids; bentonites; jelly; polycinylpyrrolidone/vinyl acetate copolymer; crospovidone; povidone; starch; pregelatinized starch; tragacanth, dextrin, a sugar, such as sucrose (for example, Dipac®), glucose, dextrose, molasses, mannitol, sorbitol, xylitol (for example, Xylitab®) and lactose; a natural or synthetic gum such as acacia, tragacanth, ghatti gum, isabgol husk mucilage, polyvinylpyrrolidone (e.g. Polycidone® CL, Kollidon® CL, Polyplasdone® XL-10), larch arabogalactan, Veegum®, polyethylene glycol, waxes , sodium alginate and the like.

A "carrier" or "carrier materials" include any excipient commonly used in pharmaceutical products and should be selected on the basis of compatibility with the compounds described herein, such as dipivephrine compounds, and release profile properties. of the desired dosage form. Illustrative carrier materials include, for example, binders, suspending agents, disintegrating agents, filling agents, surfactants, solubilizers, stabilizers, lubricants, wetting agents, diluents and the like. "Pharmaceutically compatible carrier materials" include, but are not limited to, acacia, gelatin, colloidal silicon dioxide, calcium glycerophosphate, calcium lactate, maltodextrin, glycerin, magnesium silicate, polyvinylpyrrolidone (PVP), cholesterol, cholesterol esters , sodium caseinate, soy lecithin, taurocholic acid, phosphotidylcholine, sodium chloride, tricalcium phosphate, dipotassium phosphate, cellulose and cellulose conjugates, sugars, sodium stearoyl lactylate, carrageenan, monoglyceride, diglyceride, pegelatinized starch and the like. See, for example, Remington: The Science and Practice of Pharmacy, nineteenth ed. (Easton, Pa.: Mack Publishing Company, 1995); Hoover, John E., Remington's Pharmaceutical Sciences, Mack Publishing Co., Easton, Pa. 1975; Liberman, H.A. and Lachman, L., Eds., Pharmaceutical Dosage Forms, Marcel Decker, New York, NY, 1980; and Pharmaceutical Dosage Forms and Drug Delivery Systems, 7th ed. (Lippincott Williams & Wilkins 1999).

"Dispersing agents" and/or "viscosity modulating agents" include materials that control the diffusion and homogeneity of a drug through a liquid medium or a granulation method or a mixing method. In some embodiments, these agents also facilitate the effectiveness of an erodible coating or matrix. Examples of diffusion facilitators/dispersing agents include, for example, hydrophilic polymers, electrolytes, Tween® 60 or 80, PEG, polyvinylpyrrolidone (PVP; commercially known as Plasdone®), and carbohydrate-based dispersing agents such as, for example , hydroxypropyl celluloses (e.g. HPC, HPC-SL and HPC-L), hydroxypropylmethyl celluloses (e.g. HPMC K100, HPMC K4M, HPMC K15M and HPMC K100M), sodium carboxymethylcellulose, methylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose phthalate, stearate hydroxypropylmethylcellulose acetate (HPMCAS), non-crystalline cellulose, magnesium aluminum silicate, triethanolamine, polyvinyl alcohol (PVA), vinylpyrrolidone/vinyl acetate copolymer (s630), 4-(1,1,3,3-tetramethylbutyl polymer )phenol with ethylene oxide and formaldehyde (also known as tyloxapol), poloxamers (for example, Pluronics F68®, F88® and F108®, which are block copolymers of ethylene oxide and propylene oxide); and poloxamines (e.g., Tetronic 908®, also known as Poloxamine 908®, which is a tetrafunctional block copolymer derived from the sequential addition of propylene oxide and ethylene oxide to ethylenediamine (BASF Corporation, Parsippany, NJ)), polyvinylpyrrolidone K12, polyvinylpyrrolidone K30, polyvinylpyrrolidone/vinyl acetate copolymer (S-630), polyethylene glycol, for example, polyethylene glycol may have a molecular weight of about 300 to about 6000, or about 3350 to about 4000, or about 7000 to about 5400, sodium carboxymethylcellulose, methylcellulose, polysorbate-80, sodium alginate, gums, such as, for example, gum tragacanth and gum arabic, guar gum, xanthans, including xanthan gum, sugars, cellulosic compounds, such such as, for example, sodium carboxymethylcellulose, polysorbate-80, sodium alginate, polyethoxylated sorbitan monolaurate, polyethoxylated sorbitan monolaurate, povidone, carbomers, polyvinyl alcohol (PVA), lignates, chitosans and combinations of these. Plasticizers such as cellulose or triethylcellulose can also be used as dispersing agents. Particularly useful dispersing agents in liposomal dispersions and self-emulsifying dispersions are dimyristoyl phosphatidylcholine, natural egg phosphatidylcholine, natural egg phosphatidylglycerol, cholesterol and isopropyl myristate.

Combinations of one or more erosion facilitators with one or more diffusion facilitators may also be used in the present compositions.

The term "diluent" refers to chemicals used to dilute the compound of interest prior to delivery. Diluents can be used to stabilize compounds because they can provide a more stable environment. Salts dissolved in buffered solutions (which can also provide pH control or maintenance) are used as diluents in the art, including, but not limited to, phosphate-buffered saline. In certain embodiments, diluents increase the volume of the composition to facilitate compression or create sufficient volume for a homogeneous mixture for filling capsules. Such compounds include, for example, lactose, starch, mannitol, sorbitol, dextrose, microcrystalline cellulose such as Avicel®; dibasic calcium phosphate, dicalcium phosphate; anhydrous lactose, spray dried lactose; pregelatinized starch, compressible sugar, such as Di-Pac® (Amstar); mannitol, hydroxypropylmethylcellulose, hydroxypropylmethylcellulose acetate stearate, sucrose-based diluents, icing sugar; monobasic calcium sulfate monohydrate, calcium sulfate dehydrate; calcium sulfate trihydrate, dextrates; hydrolyzed cereal solids, amylose; powdered cellulose, calcium carbonate; wisteria, kaolin; mannitol, sodium chloride; inositol, bentonite and the like.

The term "disintegrate" includes both dissolution and dispersion of the dosage form when it comes into contact with gastrointestinal fluid. "Disintegrating agents or disintegrants" facilitate the fragmentation or disintegration of a substance. Examples of disintegrating agents include a starch, for example, a natural starch such as corn starch or potato starch, a pregelatinized starch such as National 1551 or Amijel®, or sodium starch glycolate such as Promogel® or Explotab ®, a cellulose such as a wood product, crystalline methyl cellulose, for example, Avicel®, Avicel® PH101, Avicel® PH102, Avicel® PH105, Elcema® P100, Emcocel®, Vivacel®, Ming Tia® and Solka-Floc ®, methylcellulose, croscarmellose or a cross-linked cellulose, such as cross-linked sodium carboxymethylcellulose (Ac-Di-Sol®), cross-linked carboxymethylcellulose or cross-linked croscarmellose, a cross-linked starch such as sodium starch glycolate, a cross-linked polymer such as crospovidone, a cross-linked polyvinylpyrrolidone , alginate such as alginic acid or a salt of alginic acid such as sodium alginate, a clay such as Veegum® HV (magnesium aluminum silicate), a gum such as agar, guar, carob, Karaya, pectin, or tragacanth, sodium starch glycolate, bentonite, a natural sponge, a surfactant, a resin such as a cation exchange resin, citrus pulp, sodium lauryl sulfate, sodium lauryl sulfate in combined starch and the like.

"Drug absorption" or "absorption" generally refers to the process of drug movement from the site of drug administration across a barrier into a blood vessel or site of action, e.g., a drug moving from the gastrointestinal tract to the portal vein or lymphatic system and a drug that diffuses into the bloodstream through the tissues under the tongue or through the oral mucosa.

An "enteric coating" is a substance that remains substantially intact in the stomach but dissolves and releases the drug in the small intestine or colon. In general, the enteric coating comprises a polymeric material that prevents release into the low pH environment of the stomach but ionizes at a higher pH, typically a pH of 6 to 7, and therefore sufficiently dissolves in the small intestine or colon to release the active agent there.

"Erosion facilitators" include materials that control the erosion of a particular material into the gastrointestinal fluid. Erosion facilitators in general are known to those skilled in the art. Illustrative erosion facilitators include, for example, hydrophilic polymers, electrolytes, proteins, peptides and amino acids. "Filling agents" include compounds such as lactose, calcium carbonate, calcium phosphate, dibasic calcium phosphate, calcium sulfate, microcrystalline cellulose, powdered cellulose, dextrose, dextrates, dextran, starches, pregelatinized starch, sucrose, xylitol , lactitol, mannitol, sorbitol, sodium chloride, polyethylene glycol and the like.

"Flavoring agents" and/or "sweeteners" useful in the formulations described herein include, for example, acacia syrup, acesulfame K, alitame, anise, apple, aspartame, banana, bavarian cream, berries, black currant, fudge and butter, calcium citrate, camphor, caramel, cherry, cherry cream, chocolate, cinnamon, bubble gum, citrus, citrus punch, citrus cream, cotton candy, cocoa, cola, fresh cherry, fresh citrus, cyclamate, dextrose, eucalyptus, eugenol, fructose, fruit punch, ginger, glycyrrhetinate, glycyrrhizinate (licorice), grape, grapefruit, honey, isomalt, lemon, lime, lemon cream, monoammonium glycyrrhizinate (MagnaSweet®), maltol, mannitol, maple marshmallow, menthol. Peppermint Cream, Mixed Berries, Neohesperidin DC, Neotame, Orange, Pear, Peach, Peppermint, Peppermint Cream, Prosweet® Powder, Raspberry, Root Beer, Rum, Saccharin, Safrole, Sorbitol, Peppermint, Peppermint Cream, Strawberry, strawberry cream, stevia, sucralose, sucrose, sodium saccharin, saccharin, aspartame, acesulfame potassium, mannitol, talin, silitol, sucralose, sorbitol, Swiss cream, tagatose, tangerine, thaumatin, tutti frutti, vanilla, walnut, watermelon, wild cherry, wintergreen, xylitol, or any combination of these flavoring ingredients, for example, anise-menthol, cherry-anise, cinnamon-orange, cherrycinnamon, chocolate-mint, honey-lemon, lemon-lime, lemon-mint, menthol- eucalyptus, orange-cream, vanilla-mint, and mixtures of these.

"Lubricants" and "glidants" are compounds that prevent, reduce or inhibit the adhesion or friction of materials. Illustrative lubricants include, for example, stearic acid, calcium hydroxide, talc, sodium stearyl fumarate, a hydrocarbon such as mineral oil or hydrogenated vegetable oil such as hydrogenated soybean oil (Sterotex®), higher fatty acids and their metal salts. alkali and alkaline earth metals, such as aluminum, calcium, magnesium, zinc, stearic acid, sodium stearates, glycerol, talc, waxes, Stearowet®, boric acid, sodium benzoate, sodium acetate, sodium chloride, leucine, a polyethylene glycol ( for example, PEG-4000) or a methoxypolyethylene glycol such as Carbowax™, sodium oleate, sodium benzoate, glyceryl behenate, polyethylene glycol, magnesium or sodium lauryl sulfate, colloidal silica such as Syloid™, Cab-O-Sil®, a starch such as corn starch, silicone oil, a surfactant and the like.

A "measurable serum concentration" or "measurable plasma concentration" describes the concentration in blood serum or blood plasma, usually measured in mg, mg, |jg or pg/ml. "Pharmacodynamics" refers to the factors that determine the biological response observed in relation to the concentration of drug at a site of action of the therapeutic agent per ml, dl or l of blood serum, absorbed into the bloodstream after administration. As used herein, measurable plasma concentrations are generally measured in pg/ml, ng/ml or jg/ml.

"Pharmacokinetics" refers to the factors that determine the achievement and maintenance of the appropriate concentration of the drug at a site of action.

"Plasticizers" are compounds used to soften microencapsulation material or film coatings to make them less brittle. Suitable plasticizers include, for example, polyethylene glycols such as PEG 300, PEG 400, PEG 60o, PEG 1450, p Eg 3350 and PEG 800, stearic acid, propylene glycol, oleic acid, triethylcellulose and triacetin. In some embodiments, plasticizers may also function as dispersing or wetting agents.

"Solubilizers" include compounds such as tracetin, triethyl citrate, ethyl oleate, ethyl caprylate, sodium lauryl sulfate, sodium docusate, vitamin E TPGS, dimethylacetamide, N-methylpyrrolidone, N-hydroxyethylpyrrolidone, polyvinylpyrrolidone, hydroxypropylmethylcellulose, hydroxypropylcyclodextrins, Captisol, ethanol, nbutanol, isopropyl alcohol, cholesterol, bile sheets, polyethylene glycol 200-600, glycofurol, transcutol, propylene glycol and dimethyl isosorbide and the like.

"Stabilizers" include compounds such as antioxidant agents, buffers, acids, preservatives and the like.

"Steady state", as used herein, is when the amount of drug administered is equal to the amount of drug eliminated within a dosing range resulting in a plateau or constant plasma drug exposure.

"Suspending agents" include compounds such as polyvinylpyrrolidone, for example, polyvinylpyrrolidone K12, polyvinylpyrrolidone K17, polyvinylpyrrolidone K25 or polyvinylpyrrolidone K30, vinylpyrrolidone/vinyl acetate copolymer (S630), polyethylene glycol, for example, polyethylene glycol may have a molecular weight from about 300 to about 6000, or about 3350 to about 4000, or about 7000 to about 5400, sodium carboxymethylcellulose, methylcellulose, hydroxypropylmethylcellulose, hydroxymethylcellulose acetate stearate, polysorbate-80, hydroxymethylcellulose, sodium alginate, gums, such as, for example, gum tragacanth and gum arabic, guar gum, xanthans, including xanthan gum, sugars, cellulosic compounds, such as, for example, sodium carboxymethylcellulose, methylcellulose, sodium carboxymethylcellulose, hydroxypropylmethylcellulose, hydroxyethylcellulose, polysorbate-80, sodium alginate, polyethoxylated sorbitan monolaurate, polyethoxylated sorbitan monolaurate, povidone and the like.

"Surfactants" include compounds such as sodium lauryl sulfate, sodium docusate, Tween 60 or 80, triacetin, vitamin E TPGS, sorbitan monooleate, polyoxyethylene sorbitan monooleate, polysorbates, polaxomers, bile sheets, glyceryl monostearate, oxide copolymers of ethylene and propylene oxide, for example, Pluronic® (BASF), and the like. Some other surfactants include polyoxyethylene fatty acid glycerides and vegetable oils, for example, polyoxyethylene hydrogenated castor oil (60); and polyoxyethylene alkyl ethers and alkylphenyl ethers, for example, octoxynol 10, octoxynol 40. In some embodiments, surfactants are included to improve physical stability or for other purposes.

"Viscosity enhancing agents" include, for example, methylcellulose, xanthan gum, carboxymethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, hydroxypropylmethylcellulose acetate stearate, hydroxypropylmethylcellulose phthalate, carbomer, polyvinyl alcohol, alginates, acacia, chitosans and combinations thereof.

"Wetting agents" include compounds such as oleic acid, glyceryl monostearate, sorbitan monooleate, sorbitan, monolaurate, triethanolamine oleate, polyoxyethylenesorbitan monooleate, polyoxyethylenesorbitan monolaurate, sodium docusate, sodium oleate, sodium lauryl sulfate, docusate sodium, triacetin, Tween 80, vitamin E TPGS, ammonium salts and the like.

Formulations

The formulations of the dipivefrin compositions are suitable for oral administration. The formulations may conveniently be presented in unit dosage form and may be prepared by any of the methods well known in the pharmaceutical art. All methods include the step of associating a compound of the present description or a pharmaceutically acceptable salt, or solvate, hydrate, prodrug, analogue and derivatives thereof ("active ingredient") with the carrier constituting one or more accessory ingredients. In general, formulations are prepared by uniformly and intimately associating the active ingredient with liquid carriers or finely divided solid carriers or both and then, if necessary, molding the product into the desired formulation.

Formulations of dipivefrin compositions suitable for oral administration may be presented as discrete units such as capsules, capsules or tablets, each of which contains a predetermined amount of the active ingredient; as a powder or granules; as a solution or suspension in an aqueous liquid or non-aqueous liquid; or as an oil-in-water liquid emulsion or a water-in-oil liquid emulsion or submicron particles suspended in aqueous or non-aqueous liquid or complexes with cyclodextrins. The active ingredient can also be presented in the form of a bolus, electuary or paste.

Pharmaceutical preparations of dipivefrin compositions that can be used orally include tablets, snap-fit capsules made of gelatin, as well as sealed soft capsules made of gelatin and a plasticizer, such as glycerol or sorbitol. The tablets may be manufactured by compression or molding, optionally with one or more accessory ingredients. Compressed tablets may be prepared by compressing the active ingredient in a suitable machine into a free-flowing form such as a powder or granules, optionally mixed with binders, inert diluents or lubricating agents, surfactants or dispersants. Molded tablets can be manufactured by molding in a suitable machine a mixture of the powdered compound moistened with an inert liquid diluent. The tablets may optionally be coated or scored and may be formulated to provide a slow or controlled release of the active ingredient. All formulations for oral administration must be in doses appropriate for such administration. The snap-fit capsules may contain the active ingredients mixed with a filler such as lactose, binders such as starches and/or lubricants such as talc or magnesium stearate and, optionally, stabilizers. In soft capsules, the active compounds can be dissolved or suspended in suitable liquids, such as fatty oils, liquid paraffin or liquid polyethylene glycols. Additionally, stabilizers can be added. The dragee cores are provided with suitable coatings. For this, concentrated sugar solutions can be used, which may optionally contain gum arabic, talc, polyvinylpyrrolidone, gel of carbopol, polyethylene glycol and/or titanium dioxide, lacquer solutions and suitable organic solvents or mixtures of solvents. Dyes or pigments may be added to tablets or dragee coatings for identification or to characterize different dose combinations of the active compound.

Pharmaceutical preparations of dipivefrin compositions may be formulated for oral administration as orally dissolving tablets or orally disintegrating (ODT) tablets. ODTs differ from traditional tablets in that they are designed to dissolve on the tongue or disintegrate in the mouth rather than swallowed whole. ODT serves as an alternative dosage form for patients experiencing dysphagia (difficulty swallowing) or for those in whom compliance is a known problem and therefore an easier-to-take dosage form ensures that the medication. ODTs also have a faster onset of action due to pregastric absorption and potentially improved pharmacokinetics than tablets or capsules and have the convenience of a tablet that can be taken without water.

Manufacturing processes for orally dissolving dosage forms containing dipivefrin compositions suitable for oral, buccal, lingual and sublingual administration are known in the art and include, but are not limited to, conventional tableting techniques. , freeze-drying technology and thread-based tableting technology.

Conventional tablet processing features conventional tablet characteristics for ease of handling, packaging, and rapid disintegration (T.K. Ghosh, October 29, 2003, American Association of Pharmaceutical Scientists). The technology is based on a combination of physically modified polysaccharides that have water dissolution characteristics that facilitate rapid disintegration and high compressibility. The result is a rapidly disintegrating tablet that has the appropriate hardness for packaging in bottles and is easy to handle. In certain embodiments, the manufacturing process involves granulating low moldability sugars (e.g., mannitol, lactose, glucose, sucrose and erythritol) that exhibit rapid dissolution characteristics with high moldability sugars (e.g., maltose, sorbitol, trehalose and maltitol). ). The result is a mixture of excipients that have fast dissolving and highly moldable characteristics (Hamilton et al., 2005, Drug Deliv. Technol. 5: 34-37). Dipivephrine can be added, along with other standard tableting excipients, during granulation or blending processes. The tablets are manufactured with a low compression force followed by an optional moisture conditioning treatment to increase the hardness of the tablet (Parakh, et al., 2003, Pharm. Tech. 27: 92-100).

In other embodiments, an oral, buccal or sublingual tablet comprising dipivefrin is based on a conventional tableting process involving the direct compression of active ingredients, effervescent excipients and taste masking agents. The tablet disintegrates quickly because effervescent carbon dioxide is produced upon contact with moisture. The effervescent excipient (known as effervescent couple) is prepared by coating organic acid crystals using a stoichiometrically smaller amount of base material. The particle size of the organic acid crystals is carefully chosen to be larger than that of the base excipient to ensure uniform coating of the base excipient on the acid crystals. The coating process is initiated by adding a reaction initiator, which in this case is purified water. The reaction is allowed to proceed only to the point of completing the base coating on the organic acid crystals. The end point required for termination of the reaction is determined by measuring the evolution of carbon dioxide. The excipient is then mixed with the active ingredient or active microparticles and other standard tableting excipients and then compressed into tablets.

In still other embodiments, oral, buccal or sublingual tablets are manufactured by combining non-compressible fillers with a taste masking excipient and an active ingredient in a dry mixture. The mixture is compressed into tablets by using a conventional rotary tablet press. Tablets made with this process have greater mechanical resistance and are robust enough to be packaged in blister packs or bottles (Aurora et al., 2005. Drug Deliv. Technol. 5:50-54). In other embodiments, the method further incorporates flavor masking sweeteners and flavoring agents such as mint, cherry and orange. In certain embodiments, dipivephrine tablets made by this process should disintegrate in the mouth within 5-45 seconds and may be formulated to be bioequivalent to intramuscular or subcutaneous dosage forms containing epinephrine.

The lyophilization process involves the removal of water (by sublimation after lyophilization) from the liquid mixture of a drug (e.g., dipivefrin), matrix former, and other excipients that are placed in preformed blister pockets. The matrix structure formed is very porous in nature and dissolves or disintegrates rapidly upon contact with saliva (Sastry, et al., 2005, Drug Delivery to the Oral Cavity: Molecule to Market, pp. 311-316). Common matrix-forming agents include gelatins, dextrans or alginates that form glassy amorphous mixtures to provide structural strength; saccharides such as mannitol or sorbitol to impart crystallinity and hardness; and water, which functions as a manufacturing process medium during the freeze-drying stage to induce the porous structure after sublimation. Additionally, the matrix may contain flavor masking agents such as sweeteners, flavorings, pH adjusting agents such as citric acid and preservatives to ensure aqueous stability of the drug suspended in the medium prior to sublimation. In In this embodiment, lyophilized oral dissolving/disintegrating dosage forms comprising dipivefrin may be manufactured and packaged in polyvinyl chloride or polyvinylidene chloride plastic packages, or may be packaged in laminates or multilaminated aluminum foil pouches to protect the product from external humidity.

Other known methods for manufacturing ODT include lyophilization (e.g., Lyoc (Farmalyoc, now Cephalon, Franzer, PA) and QuickSolv (Janssen Pharmaceutica, Beerse, Belgium). Lyoc is a solid, porous wafer manufactured by lyophilization of an oil emulsion in water placed directly in a blister and subsequently sealed. The wafer can adapt to high doses of drug and disintegrate quickly but has low mechanical strength (see EP 0159237). QuickSolv tablets are manufactured with a similar technology that creates a porous solid matrix by freezing a dispersion or aqueous solution of the matrix formulation. The process works by removing water through the use of excess alcohol (solvent extraction).

In other embodiments, thread-based tablet technology (e.g., FlashDose, Biovail, Mississauga, ON, Canada) can be used to produce fast-dissolving lingual, buccal, or sublingual tablets comprising dipivephrine through the use of a thread known as shear-shaped matrix. This thread is commonly composed of saccharides such as sucrose, dextrose, lactose and fructose. The saccharides are converted into thread by the simultaneous action of instant melting and centrifugal force in a thermal processing machine similar to that used to make cotton candy. See US patents no. 5,587,172, 5,622,717, 5,567,439, 5,871,781, 5,654,003 and 5,622,716, each of which is specifically incorporated by reference in its entirety herein. The fibers produced are usually amorphous in nature and are partially recrystallized, resulting in a free-flowing yarn. The thread can be mixed with dipivefrin and pharmaceutically acceptable excipients, followed by compression into a tablet that has rapid dissolving characteristics.

Additional techniques may also be used to formulate the rapidly disintegrating or sublingual lingual, buccal or sublingual tablets of the present disclosure (Sastry, et al., 2000, Pharm Sci. Technol Today 3: 138-145; Chang et al., 2000, Pharmaceutical Technology 24: 52-58; Sharma et al., 2003, Pharmaceutical Technology North American 10-15; Allen, 2003, International Journal of Pharmaceutical Technology 7: 449-450; Dobetti, 2000, Pharmaceutical Technology Europe 12: 32-42; Verma and Garg, 2001, Pharmaceutical Technology On-Line 25:1-14). Direct compression, one of these techniques, requires the incorporation of a super disintegrant in the formulation, or the use of highly water-soluble excipients to achieve rapid disintegration or dissolution of the tablet. Direct compression does not require the use of moisture or heat during the tableting process, making it very useful for the formulation and compression of tablets containing moisture- and heat-labile medications. However, the direct compression method is very sensitive to changes in excipient types and proportions, and in compression force (CF), when used to achieve tablets of adequate hardness without compromising rapid disintegration capabilities. As one skilled in the art will appreciate, in order for sublingually administered tablets to release the medication dose with the maximum rate and degree of absorption, the tablet must disintegrate almost instantaneously upon insertion into the sublingual cavity. Precise selection and evaluation of the type and proportion of excipients used to formulate the tablet control the degree of hardness and the rate of disintegration. The compression force (CF) can also be adjusted to result in tablets that have lower hardness (H) and disintegrate more quickly. Unique packaging methods, such as strip packaging, may be necessary to compensate for the problem of the extreme friability of rapidly disintegrating direct compression tablets.

Pharmaceutical preparations of dipivefrin compositions may also be formulated as rapid dissolving films (FDF) or rapid dissolving films or orally dissolving films (ODF) or oral thin films for buccal, lingual and sublingual administration. These techniques are known in the art and are described, for example, in United States Patent Nos. 7,067,116; 7,025,983; 6,923,981; 6,596,298; and United States published application no. 20040247648. In such embodiments, in addition to dipivefrin, the fast-dissolving oral films may comprise a film-forming agent and at least one of the following additional ingredients: water, antimicrobial agents, plasticizing agents, flavoring agents, saliva stimulating agents, cooling agents, surfactants, stabilizing agents, emulsifying agents, thickening agents, binding agents, coloring agents, sweeteners, fragrances, triglycerides, preservatives, polyethylene oxides, propylene glycol and the like. By way of non-limiting example, the buccal, lingual or sublingual fast-dissolving oral films described herein may comprise a film-forming agent selected from pullulan, hydroxypropylmethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, polyvinylpyrrolidone, carboxymethylcellulose, polyvinyl alcohol, sodium alginate , polyethylene glycol, xanthan gum, tragacanth gum, guar gum, acacia gum, gum arabic, polyacrylic acid, methylmethacrylate copolymer, carboxyvinyl polymer, amylose, high-amylose starch, hydroxypropylated high-amylose starch, dextrin , pectin, chitin, chitosan, levan, elsinan, collagen, gelatin, zein, gluten, soy protein isolate, whey protein isolate, casein and mixtures thereof. In certain aspects, the rapidly dissolving films may further comprise a flavor masking agent, for example, an ion exchange resin. In certain embodiments, the ion exchange resins for use in the dissolution films of the present disclosure are insoluble in water and consist of a matrix pharmacologically inert organic or inorganic that contains covalently linked functional groups that are ionic or that can be ionized under appropriate pH conditions. The organic matrix may be synthetic (for example, polymers or copolymers of acrylic acid, methacrylic acid, sulfonated styrene, sulfonated divinylbenzene) or partially synthetic (for example, modified cellulose and dextrans). The inorganic matrix can also be, for example, silica gel modified by the addition of ionic groups. Covalently linked ionic groups may be strongly acidic (e.g., sulfonic acid), weakly acidic (e.g., carboxylic acid), strongly basic (e.g., quaternary ammonium), weakly basic (e.g., primary amine), or a combination of acidic and basic groups. In other aspects, rapidly dissolving films may comprise modified starches that can significantly improve the overall stability and resistance of the film to adverse factors, including heat and humidity, to improve product performance and improve shelf life. . Modified starches may also facilitate the dissolution of more solids (up to twice the amount achievable with unmodified starch) in the buccal, lingual, or sublingual film. In certain embodiments, modified starches include modified corn starches, modified tapioca starches, acid and enzyme hydrolyzed corn and/or potato starches, hypochlorite oxidized starches, acid diluted starches, ethylated starches, cross-linked starches, tapioca starches. hydroxypropylated, hydroxypropylated corn starches, pregelatinized modified starches and the like.

Pharmaceutical preparations of dipivefrin compositions suitable for buccal, lingual and sublingual administration include sublingual tablets that dissolve easily in the mouth, dissolve quickly and with little or no residue; sublingual strips, similar to tablets in that they melt easily in the mouth and dissolve quickly; multi-purpose tablets, soluble tablets for oral or sublingual (or buccal) administration, often also suitable for the preparation of injections; sublingual drops, a concentrated solution dropped under the tongue; sublingual spray, tongue spray; pills, effects of a combination of a patient-controlled rate and measurement of a sublingual, buccal and oral administration; buccal or sublingual effervescent tablets, this method carries the medication through the mucous membranes much faster.

For buccal or sublingual administration, the compositions may take the form of conventionally formulated tablets, lozenges, films or gels. Such compositions may comprise the active ingredient in a flavored base such as sucrose and acacia or tragacanth.

It should be understood that in addition to the ingredients particularly mentioned above, the compounds and compositions described in the present description may include other agents conventional in the art taking into account the type of formulation in question, for example, formulations suitable for oral administration may include agents flavorings.

The pharmaceutical compositions described herein contain the active ingredient in a form suitable for oral use, for example, as tablets, troches, lozenges, aqueous or oily suspensions, dispersible powders or granules, emulsions, hard or soft capsules, syrups or elixirs. . Compositions intended for oral use may be prepared according to any method known in the art for the manufacture of pharmaceutical compositions, and said compositions may contain one or more agents selected from the group consisting of sweetening agents, flavoring agents, coloring agents and preservatives to provide pharmaceutically elegant and palatable preparations. The tablets contain the active ingredient mixed with pharmaceutically acceptable non-toxic excipients that are suitable for tablet manufacturing. These excipients may be, for example, inert diluents, such as calcium carbonate, sodium carbonate, lactose, calcium phosphate or sodium phosphate; granulating and disintegrating agents, such as microcrystalline cellulose, croscarmellose sodium, corn starch or alginic acid; binding agents, for example starch, gelatin, polyvinylpyrrolidone or acacia, and lubricating agents, for example magnesium stearate, stearic acid or talc. The tablets may be uncoated or may be coated by known techniques to mask the taste of the drug or delay disintegration and absorption in the gastrointestinal tract and therefore provide sustained action over a longer period. For example, a water-soluble flavor masking material such as hydroxypropylmethylcellulose or hydroxypropylcellulose, or a time-retardant material such as ethylcellulose or cellulose acetate butyrate may be employed as appropriate. Formulations for oral use may also be presented as hard gelatin capsules where the active ingredient is mixed with an inert solid diluent, for example, calcium carbonate, calcium phosphate or kaolin, or as soft gelatin capsules where the active ingredient It is mixed with a water-soluble carrier such as polyethylene glycol or an oil medium, for example peanut oil, liquid paraffin or olive oil.

Aqueous suspensions contain the active material mixed with excipients suitable for the manufacture of aqueous suspensions. Such excipients are suspending agents, for example, sodium carboxymethylcellulose, methylcellulose, hydroxypropylmethylcellulose, sodium alginate, polyvinylpyrrolidone, gum tragacanth and gum arabic; The dispersing or wetting agents may be a natural phosphatide, for example, lecithin, or condensation products of an alkylene oxide with fatty acids, for example, polyoxyethylene stearate, or condensation products of ethylene oxide with long chain aliphatic alcohols. , for example, heptadecaethylene-oxycetanol, or condensation products of ethylene oxide with partial esters derived from fatty acids and such a hexitol such as polyoxyethylene sorbitol monooleate, or condensation products of ethylene oxide with partial esters derived from fatty acids and hexitol anhydrides, for example polyethylene sorbitol monooleate. Aqueous suspensions may also contain one or more preservatives, for example ethyl or n-propyl p-hydroxybenzoate, one or more coloring agents, one or more flavoring agents and one or more sweetening agents, such as sucrose, saccharin or aspartame.

Oil suspensions can be formulated by suspending the active ingredient in a vegetable oil, for example, peanut oil, olive oil, sesame oil or coconut oil, or in mineral oil such as liquid paraffin. Oily suspensions may contain a thickening agent, for example beeswax, hard paraffin or cetyl alcohol. Sweetening agents such as those set forth above and flavoring agents may be added to provide a palatable oral preparation. These compositions can be preserved by the addition of an antioxidant such as butylated hydroxyanisole or alpha-tocopherol.

Dispersible powders and granules suitable for the preparation of an aqueous suspension by the addition of water provide the active ingredient mixed with a dispersing or wetting agent, a suspending agent and one or more preservatives. Suitable dispersing or wetting agents and suspending agents are exemplified by those already mentioned above. Additional excipients may also be present, for example sweetening, flavoring and coloring agents. These compositions can be preserved by adding an antioxidant such as ascorbic acid.

Pharmaceutical compositions may also be in the form of oil-in-water emulsions. The oil phase may be a vegetable oil, for example olive oil or peanut oil, or a mineral oil, for example liquid paraffin or mixtures thereof. Suitable emulsifying agents may be natural phosphatides, for example, soy lecithin, and esters or partial esters derived from fatty acids and hexitol anhydrides, for example, sorbitan monooleate, and condensation products of said partial esters with ethylene oxide, for example, polyoxyethylenesorbitan monooleate. Emulsions may also contain sweetening agents, flavorings, preservatives and antioxidants.

Syrups and elixirs can be formulated with sweetening agents, for example, glycerol, propylene glycol, sorbitol or sucrose. Such formulations may also contain demulcent agents, preservatives, flavorings and colorings and antioxidants.

The description includes an orally dissolving tablet containing dipivefrin or a salt of dipivefrin such as dipivefrin HCl. The orally dissolving tablet may dissolve in the oral cavity in 5 minutes or less, 2 minutes or less, 1 minute or less, or 30 seconds or less. The tablet contains (based on dipivefrin free base) 1 mg to 100 mg dipivefrin, 1 mg to 50 mg dipivefrin, 1 mg to 20 mg dipivefrin, 1 mg to 10 mg dipivefrin, 5 mg of dipivefrin or 3.0 mg of dipivefrin. The orally dissolving tablet contains a water-soluble polymer, such as gelatin or HPMC. The water-soluble polymer may comprise 1% to 60% w/w, 1% to 50% w/w or 10% to 50% w/w of the tablet. The tablet may contain a sweetener, such as saccharin, sucralose, aspartame, acesulfame K, maltitol, stevia or a combination of any of the above. The tablet may contain a buffer. The tablet may contain povidone, for example 1% to 30% or 5% to 25% w/w povidone. The orally dissolving tablet may be a tablet of dipivephrine or a salt of dipivephrine that can provide substantially the same level of epinephrine in the blood as an injectable dosage form of epinephrine approved by the United States FDA within 45 minutes or within 30 minutes after administration.

Dose

The amount of pharmaceutical compositions administered will primarily depend on the mammal being treated. In cases where pharmaceutical compositions are administered to a human subject, the daily dose will generally be determined by the prescribing physician, and the dose will generally vary according to age, sex, diet, weight, health status. general health and response of the individual patient, the severity of the patient's symptoms, the precise indication or condition being treated, the severity of the indication or condition being treated, the timing of administration, the route of administration, the disposition of the composition, the excretion rate, the combination of drugs and the judgment of the attending physician. Additionally, the route of administration may vary depending on the condition and its severity. Preferably, the pharmaceutical composition is in unit dosage form. In such form, the preparation is subdivided into unit doses containing appropriate amounts of the active component, for example, an amount effective to achieve the desired purpose. Determining the appropriate dosage for a particular situation is within the skill of the art. Generally, treatment is started with smaller doses that are less than the optimal dose of the compound. Thereafter, the dose is increased in small amounts until the optimal effect is reached under the circumstances. For convenience, the total daily dose can be divided and administered in portions throughout the day if desired. The amount and frequency of administration of the compounds described herein and, if applicable, other therapeutic agents and/or therapies will be regulated according to the discretion of the attending physician (physician) taking into account the factors described above. Therefore, the amount of the pharmaceutical composition to be administered can vary widely. Administration may occur in an amount between approximately 0.001 mg/kg of body weight to about 1000 mg/kg body weight per day (administered in single or divided doses), more preferably at least about 5 mg/kg body weight per day. A particular therapeutic dosage of dipivefrin may include, for example, from about 0.01 mg to about 200 mg of the compound, or from about 0.05 mg to about 50 mg. The amount of active compound in a unit dose of preparation can be varied or adjusted according to the particular application from about 0.01 mg to 150 mg, 0.01 mg to 100 mg, 0.01 mg to 50 mg, 0.1 mg to 20 mg, 0.1 mg to 10 mg, 0.1 mg to 5 mg, 0.1 mg to 3 mg, 2.5 mg, 2 mg, or 1.5 mg of dipivefrin.

In some cases, dosage levels below the lower limit of the aforementioned range may be more than adequate, while in other cases even higher doses can be employed without causing any harmful side effects, for example, by dividing such higher doses into several small doses to administer throughout the day. The amount administered will vary depending on the particular IC50 value of the compound used. In combination applications where the compound is not the only therapy, it may be possible to administer smaller amounts of compound and still have a therapeutic or prophylactic effect.

This description is further illustrated by the following examples, which are not limiting.

Examples

Example 1. Pharmacokinetic profile of dipivefrin after a single oral administration in mice

Male C57BL6 mice, approximately 14 weeks old and weighing 28–31 g, were placed in an anesthesia chamber and transiently anesthetized with isoflurane (Henry Schein). After approximately 5 minutes and in the absence of reflex (toe pinch), blood was drawn from the mice through the retro-orbital sinus at t=0 (before administration). A volume of 25 μl of whole blood was taken from the retro-orbital sinus and added to 40 ml of saline supplemented with EDTA (0.125%) and sodium metabisulfite (1 mg/ml) (3.85x dilution). Mice (N = 3) were then immediately orally dosed with dipivephrine chloride formulated as an aqueous solution at a dose of 21.2 mg/kg (equivalent to 10 mg/kg racemic epinephrine). After oral administration, mice had retro-orbital blood drawn under anesthesia at the following time points after administration: 15, 30, 1 h, 2 h, 4 h, and 6 h. Approximately 45 μl of the diluted plasma was extracted and plated.

The presence of epinephrine in plasma samples was determined using a validated LC/MS/MS method (Keystone Bioana lytics, North Wales PA). The results of the pharmacokinetic analysis of oral dipivefrin HCl are summarized in Table 1 along with those of the IP and IM administration shown in Examples 2 and 3.

Figure 1 shows the mean plasma epinephrine concentration at time points T0 (before administration), 15, 30 min, 1, 2, 4, and 6 h. This example together with Example 2 and 3 demonstrates that dipivephrine was absorbed and biotransformed to epinephrine rapidly after oral, IM and IP administration.

Comparative Example: Example 2. Pharmacokinetic profile of dipivefrin after a single i.p. injection. in mice Male C57BL6 mice approximately 14 weeks old and weighing 28 to 31 g were placed in an anesthesia chamber and transiently anesthetized with isoflurane (Henry Schein). After approximately 5 minutes and in the absence of reflex (toe pinch), blood was drawn from the mice through the retroorbital sinus at t=0. A volume of 25 μl of whole blood was taken from the retro-orbital sinus and added to 40 μl of saline supplemented with EDTA (0.125%) and sodium metabisulfite (1 mg/ml) (3.85x dilution). Mice (N = 3) were then immediately given an intraperitoneal (IP) injection with dipivephrine chloride formulated as an aqueous solution at 1.06 mg/kg (equivalent to 0.5 mg/kg racemic epinephrine). After IP administration, mice had retro-orbital blood drawn under anesthesia at the following time points: 5, 15, 30, 1 h, 2 h, 4 h, and 6 h. Approximately 45 μl of the diluted plasma was extracted and plated.

The presence of epinephrine was detected from plasma samples using a validated LC/MS/MS method.

Figure 2 shows the mean plasma epinephrine concentration at time points T0 (before administration), 5, 15, 30 min, 1, 2, 4, and 6 h. As the data show, dipivephrine was rapidly absorbed after IP administration and was rapidly converted to epinephrine in vivo within minutes.

Comparative example: Example 3. Comparison of tolerability between dipivephrine 0.57 mg im (free base, equivalent to 0.3 mg racemic epinephrine) and epinephrine 0.3 mg im

The purpose of this example is to demonstrate that dipivephrine is better tolerated than epinephrine when administered by IM injection at the same equivalent dose of epinephrine. Six male C57BL6 mice approximately 14 weeks old and weighing 28 to 31 g were placed in an anesthesia chamber and transiently anesthetized with isoflurane (Henry Schein). After approximately 5 minutes and in the absence of reflex (toe pinch), blood was drawn from the mice through the retro-orbital sinus at t=0 (before administration). A 25 µl volume of whole blood was withdrawn from the retro-orbital sinus and added to 40 µl of saline supplemented with EDTA (0.125%) and sodium metabisulfite (1 mg/ml) (3.85x dilution).

Next, three mice were immediately given an intramuscular (IM) injection with 0.636 mg dipivephrine hydrochloride (equivalent to 0.3 mg racemic epinephrine) and three were given an IM dose of 0.546 mg epinephrine bitartrate (0.3 mg free base). After IM administration, mice were bled retroorbitally under anesthesia at the following time points: 5, 15, 30, 1 h, 2 h, 4 h, and 6 h. Approximately 45 μl of plasma (3.85x dilution, see Example 1 for details) was recovered and plated. The three mice administered dipivefrin hydrochloride appeared normal throughout the study and showed no signs of distress or illness. Animals dosed with epinephrine bitartrate were cold and lethargic approximately 5 minutes after IM injection. Two out of three mice in this group were found dead about 20 minutes after administration of the compound, with pink liquid coming from their noses and mouths. The plasma epinephrine concentration versus time profiles for the dipivephrine hydrochloride and epinephrine bitartrate groups are shown in Figures 3A and 3B, respectively. Consistent with the data in Figure 3A, dipivephrine hydrochloride was rapidly absorbed upon IM injection and was rapidly converted to epinephrine. Figure 3B shows that IM injection of epinephrine at the same equivalent dose of 0.3 mg resulted in a plasma epinephrine concentration approximately 10,100 times that of dipivephrine (Cmax), which would explain the acute toxicity of IM epinephrine. . This example illustrates the danger of a possible accidental overdose of epinephrine administered by IM injection as a result of the rapid increase of epinephrine in the blood to a lethal level. On the other hand, the safety risk of overdose from I ^m administration of dipivephrine is greatly reduced since the conversion to epinephrine is regulated by the availability of the enzymes that are responsible for the conversion of the prodrug to epinephrine. Therefore, we believe that dipivephrine is a safer source of epinephrine when administered by injection than direct injection of epinephrine, given the potential risks of overdose with direct injection of epinephrine.

Example 4. Evaluation of the activity of dipivefrin as a single agent in the treatment of B16-F10 syngeneic melanoma subcutaneous tumors in the stages of tumor induction and development in C57BL/6J mice

This preclinical study evaluates the in vivo therapeutic activity of dipivephrine 15.3 mg/kg (free base, equivalent to 8 mg/kg racemic epinephrine) administered orally as a single agent in the treatment of subcutaneous B16-F10 syngeneic melanoma tumors. in the stages of tumor induction and development in C57BL/6J mice. The experimental design of the study is summarized in table 2.

Treatments were started 7 days before tumor inoculation according to the study design (day - 7). The administration of the test article and the number of animals in each study group are shown in Table 3.

Study endpoints included the following: tumor growth inhibition (TGI); median reduction in tumor volume on a given day; The survival of all animals will be followed and the mean survival time (MST) and increased life expectancy (ILS) will be calculated for each group.

The percentage of tumor growth inhibition (TGI%) is an indication of antitumor efficacy and is expressed as:

TGI (%) = 100 x (1-T/C), where T and C are the mean tumor volume of the treated and control groups, respectively, on a given day.

The endpoint for each mouse is a tumor volume > 3000 mm3 or that the animal experiences extreme suffering (such as pain, seizures, difficulty breathing, etc.). Increased life expectancy (ILS) is calculated as follows: ILS (%) = 100 x [(median survival time of the drug group/median survival time of the vehicle group) -1 ] (%)

Female C57BL/6J mice (Shanghai Lingchang Bio-Technology Co. Ltd (LC, Shanghai, China; Animal Certificate No.: 2013001825675) were used in the study. At the time of inoculation, the mice were 7 8 weeks old and a body weight of 16.2-18.6 g. Mice were maintained in an individually ventilated cage (IVC) system at constant temperature (22~24°C) and humidity (60-70%) with 5 animals in each cage. The animals had free access throughout the study period to a standard mouse diet (a dry pelleted food sterilized by Co60 radiation) and water.

The test articles used in the study were dipivefrin hydrochloride (free base at 1.9 mg/mL, preformulated dosing solution) or the vehicle (purified water containing 0.005 wt% benzalkonium chloride as a preservative). Each was stored at 4°C. B16-F10 tumor cells were maintained in vitro as a monolayer culture in DMEM medium supplemented with 10% fetal bovine serum at 37°C in an atmosphere of 5% CO ² in air. Tumor cells were routinely subcultured twice a week. Cells growing in an exponential growth phase were harvested and counted for tumor inoculation.

Each mouse was inoculated subcutaneously in the right flank region with 2x 105 B16F10 tumor cells in 0.1 ml of PB S for tumor development. Treatments were started 7 days before inoculation. The test article was administered to the tumor-bearing mice according to the predetermined regimen as shown in Study Design Table 3. The date of inoculation of the tumor cells was called day 0. First grouping: On day 7, all 30 animals were weighed and body weight was used as a numerical parameter to randomize the selected animals into two groups in an effort to minimize error. systematic. The dosage was administered as indicated in Table 4.

Note: N: number of animals.

Second grouping: On day 8, the 20 animals in group-1 were randomly distributed into two groups (1a and 1b) based on tumor volume. Dose administrations were performed as shown in Table 5.

Both randomization procedures were performed using STUDYDIRECTOR™ software (Studylog Systems, Inc. CA, United States). An optimal randomization design (generated by the paired distribution method) that showed minimal group-to-group variation in body weight or tumor volume was selected for assignment to groups.

Treatment was started 7 days before inoculation according to the study design (Table 2).

After inoculation of tumor cells, animals were monitored daily for morbidity and mortality. At the time of routine monitoring, animals were monitored for any effects of tumor growth and treatments on normal behavior, such as mobility, food and water consumption, body weight gain/loss (the body weights were measured two to three times a week), eye discharge/matted hair, and any other abnormal effects. Death and clinical signs observed were recorded based on the number of animals within each subset.

Tumor volumes were measured two to three times a week in two dimensions by using a caliper, and the volume in mm3 was estimated by using the formula: V = 0.5 ax b2 where a and b are the perpendicular diameters long and short of the tumor, respectively. Dosing procedures, as well as tumor and body weight measurement, were performed in a laminar flow cabinet.

On day 17, mice whose tumor volumes exceeded 3000 mm3 were sacrificed and the entire study ended on day 19. Furthermore, mouse #15 in group 1-b was dead on day 13 due to operation error, while Mouse #7 in group 1-a was found dead on day 18 due to tumor ulceration.

Statistical analysis of the difference in tumor volume between groups was performed on the data obtained on day 5, day 14, and day 19 after tumor inoculation by using the independent samples T test or the the median of Mood.

Survival time was analyzed by the Kaplan-Meier method. The event of interest was the end point of reaching an individual tumor volume of 3000 mm3 or the death of the animal. Survival time was defined as the time from the day after tumor cell inoculation to the day of death or euthanasia of the animal. For each group, median survival time (MST), its corresponding 95% confidence interval, and increased life expectancy (ILS) were calculated. Kaplan-Meier curves were also constructed for each group, and the log-rank test was used to compare survival curves between groups.

All data were analyzed in SPSS (Statistical Product and Service Solutions) version 18.0 (IBM, Armonk, NY, United States) or GRAPHPAD PRISM 5.0. P values were rounded to three decimal places, with the exception of raw p values less than 0.001 which were reported as P<0.001. All tests were bilateral. P<0.05 was considered statistically significant.

No body weight differences were observed between treatment groups during treatments in both tumor induction and development (See Figure 4) and no drug-related deaths were observed during the study period. Therefore, daily administration of dipivefrin hydrochloride at 15.3 mg/kg (free base) has no effect on body weight.

Oral administration of dipivefrin was also shown to significantly inhibit B16F10 tumor formation after inoculation of tumor cells. Figure 5 shows the mean tumor volumes of mice treated with dipivefrin and vehicle 5 days after inoculation of B16F10 tumor cells. As the data show, mice treated with dipivefrin hydrochloride showed significantly lower tumor volume than mice treated with vehicle (6.2 ± 1.1 mm3 vs. 16.4 ± 2.5 mm3, p < 0.01, independent t test) during the initial stage of tumor induction. This observation suggests that dipivefrin induced the destruction of cancer cells at the inoculation site.

Oral administration of dipivefrin also resulted in a significant reduction in median tumor volume, compared to vehicle, 14 days after inoculation of B16F10 tumor cells into mice. Figure 6 shows the median tumor volumes of mice treated with dipivefrin and vehicle 14 days after inoculation of B16F10 cancer cells. As the data show, mice treated with dipivefrin showed a significantly lower median tumor volume than mice treated with vehicle (827 mm3 vs 1060 mm3, p<0.05, Mood's median test).

Oral administration of dipivefrin has also been shown to inhibit the growth of B16F10 tumors after the tumor has established. Vehicle-treated mice (group 1, N=20) were randomized into two equal groups of 10 each (1a and 1b) 8 days after B16F10 tumor inoculation based on tumor volume (mean tumor volume 145.5 ± 30.8 mm3 for group 1a vs 145.6 ± 35.6 mm3 for group 1b). While mice in group 1a continued to receive vehicle, mice in group 1b received daily oral dipivefrin starting on day 8. On day 19, the dipivefrin-treated group had an approximately 18% reduction in mean tumor volume compared with the vehicle-treated group (2997.2 ± 341.6 mm3 vs. 3668.0 ± 311.9 mm3). The data is also shown in Figure 7.

Oral administration of dipivefrin significantly prolonged survival time compared to vehicle in the treatment of B16F10 subcutaneous tumors in C57BL/6J mice. The survival times of the different groups are shown in Table 6. The Kaplan-Meier survival curves of these groups are shown in Figure 8. The log-rank test was used to compare the survival curves between groups. Group 1b treated with dipivefrin demonstrated a significant increase in lifespan (ILS) compared to group 1a treated with vehicle (12%, p = 0.038). Group 2 treated with dipivefrin showed a 6% increase in lifespan compared to vehicle. Although this increase in lifespan did not reach statistical significance (p = 0.175), it supports the fact that dipivefrin provides survival benefits compared to vehicle. The survival times of the two groups 1a and 2 treated with dipivefrin are not statistically different as expected (p = 0.448).

Example 5 efficacy of dipivefrin for the treatment of influenza a(H1N1pdm) virus infection in C57BL/6 mice

These experiments demonstrate that oral treatment of mice with dipivefrin can help prevent death and reduce body weight loss due to influenza. The effect of dipivephrine on A/California/04/2009 (H1N1pdm) virus infection was tested in C57BL/6J mice.

Twelve female C57BL/6J mice from Jackson Laboratories (Bar Harbor, ME, 18–20 g) were anesthetized by i.p. of ketamine/xylazine (50/5 mg/kg) followed by intranasal (i.n.) exposure to a 75 μl suspension of influenza virus. The infectious inoculum of the virus is a challenge dose of 90% lethality based on the results of a previous titration study in mice. Six mice were administered dipivephrine HCl (0.16 ml, formulated as a 1.06 mg/ml solution equivalent to 0.5 mg/ml epinephrine) p.o. once 24 hours after infection at a dose of 8.48 mg/kg (equivalent to 4 mg/kg epinephrine). A placebo (compound vehicle only) was administered at the same dosing regimen to the other six mice. Three mice each from the treated group and the placebo group were sacrificed on day 3 and day 6 postinfection (p.i.) and lung tissue was sampled. The tissue was weighed and given a hemorrhage score from 0 (unaffected) to 4 (all four lobes, or the entire lung, had a discolored/darkened appearance). Lungs were weighed and frozen at −80°C.

Lung tissue was thawed and homogenized in 1 ml of cell culture medium and titers were determined in the homogenate by end-point dilution (10-fold dilutions) in 96-well microplates seeded with confluent MDCK cells. The culture medium was MEM with porcine trypsin at 10 Ul/ml, EDTA at 1 pg/ml and gentamicin at 50 pg/ml. The plates were incubated at 37°C for 5 days and then the viral cytopathic effect was read in each well. The fifty percent infectious dose of the cell culture (CCID ⁵⁰ ) of each lung was determined by using the Reed-Muench equation.

Statistical analysis of data: Individual body weight percentages were calculated from day 0 weights. Statistical analyzes of mouse weight and lung virus titers were performed by using two-way ANOVA followed by posterior Bonferroni multiple comparisons. Statistical comparisons were made between the treated and placebo groups. All statistical analyzes were performed using Prism 7.0 (GraphPad Software, San Diego, CA).

The body weight changes during infection are graphically shown in Figure 10. The body weights of the mice differed significantly between the treatment and placebo groups on days 5 and 6 p.i. (p<0.05), and mice treated with dipivefrin lost less weight during the 6 days of observation.

Visual pulmonary hemorrhage scores ranged from 0-3 in both treatment groups. Influenza virus titers in lung tissues did not differ significantly between the treated and placebo groups on day 3 or 6 p.i. (Figure 11). The drug-treated group had lower viral titers in lung tissues on day 6 p.i. that on day 3 p.i. (p<0.05). Pulmonary viral titers did not differ significantly between these two days p.i. for the placebo group (p=0.42). Of note, one treated mouse maintained its body weight during the challenge period, despite having pulmonary viral titers on day 6 p.i.

Briefly, in this study, mice were treated with a single dose of 8.48 mg/kg dipivefrin HCl 24 hours after virus exposure. Treated mice were less sick, as evidenced by less weight loss compared to placebos (p<0.05). Average lung virus titers on day 6 were slightly lower in treated mice compared to placebo, the difference was not statistically significant. The drug-treated group had significantly lower virus titers in lung tissues on day 6 p.i. that on day 3 p.i. (p<0.05). Pulmonary viral titers did not differ significantly between these two days p.i. for the placebo group (p=0.42). Of note, one treated mouse maintained its body weight during the challenge period, despite having pulmonary viral titers on day 6 p.i.

Example 6. Antibacterial activity of dipivefrin in a peritonitis-sepsis model of MRSA infection This example demonstrates the in vivo antibacterial activity of dipivefrin.

Two (2) groups of 6 to 8 week old female C57BL/6J mice (approx. 20 g body weight) with 10 mice/group were injected IP with 2 x108 CFU/ml of infection-resistant Staphylococcus aureus . methicillin (MRSA) NRS71-Sanger 252 in a volume of 200 pl. The treatment group received a dipivefrin dose of 15.3 mg/kg (free base) by oral gavage starting at t = -5 days relative to bacterial inoculation. Dosing occurred once daily until 7 days after bacterial inoculation. Body weights were measured once daily on days 0 to 7, and the experimental endpoint was 7-day survival. Animals that fell below 20% of original weight after infection were euthanized. Four hours (4 hours) after infection, blood was drawn from 4 animals in each group and the bacterial load was determined via a standard plaque assay. Each blood sample was diluted by serial log dilutions and 10 dilutions (100 to 10.9) were plated in duplicate in TSA with 5% sheep blood. The plates were incubated for 24 hours at 37 °C, at which time the colonies formed were enumerated and the CFU/ml was determined. One mouse in the vehicle group was found dead the day after infection, and no subsequent death occurred until 7 days after infection. No mice died in the treatment group up to 7 days after infection. Blood bacterial counts 4 hours after infection were significantly higher for the vehicle-treated group than for the drug-treated group (p < 0.05, two-tailed independent t test, Figure 9).

Example 7. Preparation of dipivefrin hydrochloride oral dissolution tablets

Gelatin (100 mg) was first dissolved in deionized water (5.0 g) at 40 °C to obtain a clear solution. Next, other inactive ingredients listed in Table 7 were added and dissolved in the gelatin solution at room temperature. Dipivefrin hydrochloride (635.2 mg) was added and dissolved last to obtain the drug solution which was dispensed into blister pockets (593.5 mg/pocket) by using a pipette. The filled blister was placed on dry ice for 2 h and transferred to a lyophilization flask that was connected to a multiple lyophilizer and lyophilized for 24 h. The tablets thus obtained containing 63.5 mg of dipivefrin HCl per tablet can be easily removed from the blister and stored in a glass bottle. The tablets were inspected for surface smoothness/sleekness and fragility. Orally dissolving dipivefrin HCl 5 mg tablets were prepared in the same manner except that 535 mg of the drug solution was dispensed into each pocket of the blister.

In vitro dissolution tests. One tablet was carefully dropped into 2 ml of gently shaken simulated saliva preheated to 37°C. The time to complete tablet dissolution was recorded by using a smartphone timer.

In vivo dissolution/flavor tests. One tablet was placed on the tongue of a healthy adult volunteer. The mouth was kept closed without chewing or swallowing. The time to complete tablet dissolution was recorded by using a smartphone timer. Subsequently, the subject's mouth was inspected for any signs of undissolved tablet residue. The volunteer was then asked to describe the taste, mouthfeel, and possible irritation.

Example 8. Pharmacokinetic studies of dipivefrin after single oral administration in rabbits

Female New Zealand white rabbits, 3.2 months old and weighing between 3.4 and 3.6 kilograms at the beginning of the study, were used for this study. Animals were identified by ear markings and cage tags. The animals were healthy at the beginning of the study. The animals were housed one per cage within the same room. Primary enclosures were as specified in the USDA Animal Welfare Act (9 CFR, Parts 1, 2, and 3) and as described in the Guide for the Care and Use of Laboratory Animals (ILAR publication, 2011, National Academy Press). Animals received a certified laboratory diet (HF 5325 Certified Rabbit Diet). Water was provided ad libitum to the animals. Two groups of animals were administered dipivephrine HCl orally formulated as a 2.12 mg/ml solution (equivalent to 1 mg/ml racemic epinephrine free base) in purified water via an oral gavage tube. gum followed by a 5 ml rinse with water. A third group of animals was administered dipivefrin HCl orally formulated as an orally dissolving tablet. The animals were immobilized manually by using cloth restraints. Dosing occurred at 0 hours on the appropriate day according to the study design shown in Table 8.

Whole blood samples (~0.5 to 1 ml) were collected from the animal's ear vessel by direct venipuncture at the appropriate time point and placed in K ² EDTA tubes as an anticoagulant. Blood samples were centrifuged at 4 °C at 3000 g for 5 minutes. All samples were kept refrigerated throughout processing. Plasma samples (250 μl) were aliquoted into 50 μl of 6 wt % sodium metabisulfite solution in an eppendorf tube and placed in a freezer to be kept at ~ -70 °C until shipping on dry ice. to Keystone Bioanalytical for the analysis of plasma epinephrine concentrations.

The results of the PK analysis are summarized in Table 9.

Cmax: maximum plasma concentration (mean ± SEM of Cmax values of individual rabbits); Tmax: time at which maximum plasma epinephrine concentration was reached (mean ± SEM of Tmax values of individual rabbits); AUCü.last: area under the plasma concentration versus time curve (mean 6 SEM of the AUC values of individual rabbits). Tmax is the time at which the maximum concentration of epinephrine occurred in each individual rabbit. Tmax is limited by the experimental design because it is a discrete variable based on defined times of blood sampling.

The mean plasma epinephrine concentration versus time profiles are shown in Figures 12-14. This example demonstrates the following: (a) the bioavailability of epinephrine increases with the dose of dipivephrine HCl after oral administration; (b) at the same dose, dipivefrin HCl oral dissolution tablet provides much greater bioavailability of epinephrine than dipivefrin HCl oral solution administered by oral gavage; (c) Compared to IM epinephrine 0.3 mg, the standard treatment for anaphylaxis, dipivephrine HCl 63.5 mg orally dissolving tablet appears to release epinephrine into the bloodstream for a longer period of time, resulting in resulting in a lower but overall comparable Cmax or even higher AUC in rabbits.

The slow release of epinephrine into the bloodstream after oral administration of dipivefrin HCl in rabbits is surprising given the fact that epinephrine is rapidly released when dipivefrin HCl is administered into the rabbit eye (Anderson, JA et al., Invest Ophthalmol Vis Sci. 1980, 19:817-23). Butyrylcholinesterase (BChE, EC 3.1.1.8) is believed to play a major role in the conversion of dipivephrine to epinephrine in the rabbit cornea (Nakamura M., et al., Ophthalmic Res 1993;25:46-51). The low Cmax and prolonged Tmax of epinephrine after oral administration of dipivephrine HCl would have made it unsuitable as oral therapy for the emergency treatment of anaphylaxis. In an anaphylactic episode, rapid release of epinephrine is essential.

Without wishing to be bound by theory, the inventor had hypothesized that the slow release of epinephrine after oral administration of dipivephrine HCl in rabbits could be caused by the relatively low activity of butyrylcholinesterase (BChE, EC 3.1.1.8). in rabbit plasma. Because the predominant cholinesterase in rabbit plasma is acetylcholinesterase (AChE; EC 3.1.1.7) as reported by Oropesa A. L., et al. (Ecotoxicol Environ Saf. 2014, 100:39-43), rabbits are not a Appropriate pharmacokinetic model for oral dipivefrin HCl.

Example 9. Pharmacokinetic studies of dipivefrin after single oral administration in dogs

The pharmacokinetics of dipivefrin HCl were evaluated in dogs in a three-legged crossover design according to the Table 10 below. Four days before the start of the study, 1 ml of whole blood was collected from four (n=4) non-virgin male Beagle dogs, 1.5-6.5 years of age and weighing between 9.8 and 10 .8 kilograms, in 4 cooled tubes containing K ² EDTA. The blood was processed to obtain plasma and plasma cholinesterase activity was analyzed according to the method of Ellman using acetylthiocholine iodide as a substrate (Ellman, GL et al., Biochemical Pharmacology, 1961, volume 7, pages 88- 95). The results of the assay are summarized in Table 10. Based on the results of the plasma cholinesterase activity assay, the top three dogs with the highest plasma cholinesterase activity were selected for the PK study.

Dogs were housed one per cage and identified by ear markings and cage tags. The animals were healthy at the beginning of the study. Primary enclosures were as specified in the USDA Animal Welfare Act (9 CFR, Parts 1, 2, and 3) and as described in the Guide for the Care and Use of Laboratory Animals (ILAR publication, 2011, National Academy Press). Animals were fasted for a minimum of 12 hours before dosing and up to 4 hours after administration; Water was provided ad libitum to the animals.

Administration occurred at 0 hours on the appropriate day according to the study design table (Table 11). The first dose of epinephrine IM 0.3 mg, standard care for anaphylaxis, is included as a control. The intramuscular dose was administered via a 25-gauge needle and syringe into the lateral aspect of the left or right thigh. The hair at the administration site was clipped and cleaned with alcohol before administration. The orally dissolving tablets were administered by placing one tablet on the dog's tongue. The snout was held gently closed for 1-2 minutes. After this period, the mouth was opened to observe that the tablet had completely dissolved.

Whole blood samples (~0.5 to 1 ml) were removed from the dog's jugular vein by direct venipuncture at the appropriate time point and placed in tubes with K ² EDTA as an anticoagulant. Blood samples were centrifuged at 4 °C at 3000 g for 5 minutes. All samples were kept refrigerated throughout processing. Plasma samples (250 μl) were aliquoted into SOuL of a 6 wt % sodium metabisulfite solution in an eppendorf tube and placed in a freezer configured to maintain ~ -70 °C until shipping on dry ice. to Keystone Bioanalytical for the analysis of plasma epinephrine concentrations.

Cmax: maximum plasma concentration (mean ± SEM of Cmax values from individual dogs); Tmax: time at which maximum plasma epinephrine concentration was reached (mean ± SEM of Tmax values from individual dogs); AUCü.last: area under the plasma concentration versus time curve (mean ± SEM of AUC values from individual dogs). Tmax is the time at which the highest maximum epinephrine concentration was reached in each individual dog. Tmax is limited by the experimental design because it is a discrete variable based on defined times of blood sampling.

The results of the pharmacokinetic analysis of dipivefrin HCl in dogs are summarized below (Table 12). Statistical analyzes were performed using one-way ANOVA followed by Tukey's multiple comparisons test. All statistical analyzes were performed using Prism 7.0 (GraphPad Software, San Diego, CA).

Following administration of an oral dissolution tablet of dipivefrin HCl to beagle dogs, the plasma epinephrine concentration increases rapidly. The orally dissolved dipivephrine HCl 5 mg tablet dose provided 2-fold the Cmax and AUCultimate compared to the standard IM injection of epinephrine 0.3 mg with a comparable Tmax. Dipivephrine HCl 63.6 mg produced significantly higher levels of epinephrine compared to dipivephrine HCl 5 mg orally dissolving tablet (p < 0.05 for Cmax and p < 0.01 for AUC) or standard epinephrine IM 0 .3 mg (p < 0.01 for Cmax and AUC). There is no significant difference in Tmax between all treatment groups (p>0.6). This example demonstrates that an ODT of dipivephrine HCl can produce statistically equivalent levels of epinephrine in dogs to standard epinephrine IM 0.3 mg, a drug of choice for the emergency treatment of anaphylaxis. See Figure 15 and 16.

This description also covers the following aspects.

The invention includes orally administered dipivephrine or a pharmaceutically acceptable salt thereof for the systemic administration of a therapeutically effective amount of epinephrine to a subject.

The invention includes orally administered dipivephrine or a pharmaceutically acceptable salt thereof for the systemic administration of a therapeutically effective amount of epinephrine to a subject, wherein the subject has an epinephrine-sensitive condition.

The condition may be difficulty breathing associated with anaphylaxis, asthma, bronchitis, emphysema, diphtheria, or respiratory infection.

The condition may be anaphylaxis. The condition may be anaphylaxis and the therapeutically effective amount of epinephrine is an amount sufficient to relieve at least one symptom of anaphylaxis in the subject. The condition may be anaphylaxis and the therapeutically effective amount of epinephrine is an amount sufficient to reduce the severity of anaphylaxis or inhibit the occurrence of anaphylaxis in the subject after exposure of the subject to an allergen. The epinephrine-sensitive condition may be cancer. The cancer can be skin cancer, brain cancer, glioma, sarcoma, breast cancer, lung cancer, non-small cell lung cancer, mesothelioma, appendiceal cancer, genitourinary cancer, renal cell carcinoma, prostate cancer. , bladder cancer, testicular cancer, penile cancer, cervical cancer, ovarian cancer, von Hippel Lindau disease, head and neck cancer, gastrointestinal cancer, hepatocellular carcinoma, gallbladder cancer, liver cancer esophagus, gastric cancer, colorectal cancer, pancreatic cancer, a neuroendocrine tumor, a thyroid tumor, a pituitary tumor, an adrenal tumor, a hematological malignancy, a lymphoma, a leukemia, or a combination of these. The condition may be skin cancer and skin cancer is melanoma. Dipivephrine or its pharmaceutically acceptable salt may be an adjuvant antineoplastic treatment and the treatment may comprise administering at least one additional antineoplastic treatment to the subject.

The epinephrine-sensitive condition may be a microbial infection. The microbial infection can be a bacterial, viral, fungal or parasitic infection. The microbial infection may be a viral infection, such as a flu infection. The microbial infection may be a bacterial infection, such as a methicillin-resistant Staphylococcus aureus (MRSA) infection. Dipivephrine or its pharmaceutically acceptable salt may be an adjuvant antimicrobial agent and the treatment may further comprise the use of at least one additional antimicrobial agent to treat the infection in the subject. The additional antimicrobial agent may be an antibiotic. The additional antimicrobial agent may be an antiviral agent.

The dipivephrine described may be racemic dipivephrine or L-dipivephrine. The dipivefrin described may be dipivefrin hydrochloride or L-dipivefrin hydrochloride. The described dipivefrin may be isotope-labeled dipivefrin or a pharmaceutically acceptable salt thereof.

The described dipivefrin may be in the form of an oral solution, a tablet or a capsule. The dipivefrin used may be in the form of an oral solution. The dipivefrin used may be in the form of an orally dissolving tablet or an orally disintegrating tablet. The dipivefrin dosage form used may comprise 0.01 mg to 150 mg, 0.01 mg to 100 mg, 0.01 mg to 50 mg, 0.1 mg to 20 mg, 0.1 mg to 10 mg, from 0.1 mg to 5 mg, from 0.1 m g or 3 mg, 2.5 mg, 2 m g or 1.5 m g dipivefrin.

The therapeutically effective amount of dipivephrine or a salt thereof may be an amount sufficient to provide a plasma anepinephrine Cmax of 0.1 to 50.0 ng/ml in the subject. The therapeutically effective amount of dipivephrine or a salt thereof may be an amount sufficient to provide a pharmacokinetic profile substantially equivalent to the epinephrine pharmacokinetic profile of a US FDA-approved injectable dosage form comprising epinephrine, when the dosage form Injectable drug approved by the US FDA is for intramuscular or subcutaneous administration. The US FDA-approved dosage form may comprise a 0.3 mg, 0.15 mg, or 0.1 mg epinephrine dosage form for intramuscular administration. The US FDA-approved dosage form may comprise a 0.3 mg, 0.15 mg, or 0.1 mg epinephrine dosage form for subcutaneous administration. This description includes the oral administration of dipivephrine or its salt to provide a therapeutically effective amount of epinephrine within 45 minutes after administration, 30 minutes after administration, within 15 minutes after administration, within 10 minutes after administration or within 5 minutes after administration.

The disclosure provides an orally dissolving tablet comprising dipivefrin or a salt of dipivefrin in a matrix that can dissolve in the oral cavity in 2 minutes or less. Certain dosage forms of the disclosure include a tablet comprising dipivefrin HCl. The dipivefrin or dipivefrin salt tablet further comprises a water-soluble polymer and a sweetener. The water-soluble polymer may be gelatin, HPMC or a combination of the above.

The compositions, methods and articles, alternatively, may comprise, consist of, or consist essentially of any appropriate materials, steps or components described herein. The compositions, methods and articles may be additionally, or alternatively, formulated so that they are devoid of, or substantially free of, any material (or species), step or component that is not otherwise necessary to achieve the function or objectives of the compositions. compositions, methods and articles.

All ranges described herein include the endpoints, and the endpoints may be combined independently of each other (for example, the ranges from "up to 25% by weight or, more specifically, 5% by weight to 20% by weight", include the extreme points and all intermediate values of the ranges of "5% by weight to 25% by weight", etc.). The values described herein include an acceptable error range for the particular value determined by one skilled in the art, which will depend in part on how the value is measured or determined, that is, the limitations of the measurement system. Reference throughout the specification to "some embodiments", "a embodiment", etc., means that a particular element described in relation to the embodiment is included in at least one embodiment described in the present description, and may or may not be present in other modalities. Furthermore, it should be understood that the described elements may be combined in any suitable manner in the various embodiments.

Although particular embodiments have been described, substantial alternatives, modifications, variations, improvements and equivalents may arise that are not currently or cannot be foreseen by applicants or others skilled in the art. Accordingly, the appended claims, as presented and as they may be amended, are intended to encompass all such alternatives, modifications, variations, improvements and substantial equivalents.

Claims (15)

1. Dipivephrine or a pharmaceutically acceptable salt thereof for use in a method of systemic delivery of a therapeutically effective amount of epinephrine to a subject, wherein said method said dipivephrine or a pharmaceutically acceptable salt thereof is administered orally. 2. Dipivephrine or salt thereof for use according to claim 1, wherein the subject has anaphylaxis; shortness of breath associated with asthma, bronchitis, emphysema, diphtheria, or respiratory infection; cancer; or a microbial infection, such as a bacterial, viral, fungal or parasitic infection. 3. Dipivephrine or salt thereof for use according to claim 2, wherein the subject has anaphylaxis, and the therapeutically effective amount of epinephrine is: (i) an amount sufficient to relieve at least one symptom of anaphylaxis in the subject; either (ii) an amount sufficient to reduce the severity of anaphylaxis or inhibit the occurrence of anaphylaxis in the subject upon exposure of the subject to an allergen. 4. Dipivephrine or salt thereof for use according to claim 2, wherein the subject has cancer. 5. Dipivephrine or salt thereof for use according to claim 4, wherein the cancer is skin cancer, brain cancer, a glioma, a sarcoma, breast cancer, lung cancer, non-small cell lung cancer, mesothelioma , appendiceal cancer, a genitourinary cancer, a renal cell carcinoma, prostate cancer, bladder cancer, testicular cancer, penile cancer, cervical cancer, ovarian cancer, von Hippel Lindau disease, a head and neck cancer , a gastrointestinal cancer, a hepatocellular carcinoma, gallbladder cancer, esophageal cancer, gastric cancer, colorectal cancer, pancreatic cancer, a neuroendocrine tumor, a thyroid tumor, a pituitary tumor, an adrenal tumor, a hematological malignancy, a lymphoma, leukemia or a combination of these. 6. Dipivephrine or salt thereof for use according to claim 4 or claim 5, wherein the dipivephrine or its pharmaceutically acceptable salt is an adjuvant antineoplastic treatment and the method comprises administering at least one additional antineoplastic treatment to the subject. 7. Dipivephrine or salt thereof for use according to claim 2, wherein the subject has a microbial infection, optionally wherein the infection is a flu infection or a methicillin-resistant Staphylococcus aureus (MRSA) infection. 8. Dipivephrine or salt thereof for use according to claim 7, wherein the dipivephrine or its pharmaceutically acceptable salt is an adjuvant antimicrobial agent and the method further comprises the use of at least one additional antimicrobial agent, such as an antibiotic or an antiviral agent, to treat the infection in the subject. 9. Dipivefrin or salt thereof for use according to any one of claims 1 to 8, wherein the dipivefrin is L-dipivefrin hydrochloride. 10. Dipivefrin or a salt thereof for use according to any one of claims 1 to 9, wherein the dipivefrin or a salt thereof is administered as an oral dosage form, wherein the dipivefrin is in the form of an oral solution, a tablet or a capsule, preferably wherein the dipivephrine or salt thereof is in the form of an orally dissolving tablet or an orally disintegrating tablet. 11. Dipivephrine or salt thereof for use according to claim 10, wherein the dipivephrine is in the form of an orally dissolving tablet comprising dipivephrine or salt thereof in a matrix that can dissolve in the oral cavity within 2 minutes or less. 12. Dipivephrine or a salt thereof for use according to claim 11, wherein the tablet further comprises a water-soluble polymer, such as gelatin, HPMC or a combination thereof, and a sweetener. 13. Dipivefrin or a salt thereof for use according to any one of claims 1 to 12, wherein the dipivefrin or a salt thereof comprises a dosage form comprising 0.01 mg to 150 mg, 0.01 mg to 100 mg, 0.01 mg to 50 mg, 0.1 mg to 20 mg, 0.1 mg to 10 mg, 0.1 mg to 5 mg, 0.1 mg to 3 mg, 2.5 mg, 2 mg or 1.5 mg of dipivefrin. 14. Dipivephrine or salt thereof for use according to any one of claims 1 to 13, wherein the subject is a human or a dog. 15. Dipivephrine or salt thereof for use according to any one of claims 1 to 14, wherein the The method provides a therapeutically effective amount of epinephrine within 30 minutes of administration, within 15 minutes of administration, within 10 minutes of administration, or within 5 minutes of administration.